Anda di halaman 1dari 17


discussions, stats, and author profiles for this publication at:

Complex and differential glial responses in

Alzheimers disease and ageing

Article in Current Alzheimer research April 2016

Impact Factor: 3.89 DOI: 10.2174/1567205013666160229112911



5 authors, including:

Arthur M Butt Vladimir Parpura

University of Portsmouth University of Alabama at Birmingham


Alexei Verkhratsky
The University of Manchester


Available from: Alexei Verkhratsky

Retrieved on: 19 May 2016
Send Orders for Reprints to
Current Alzheimer Research, 2016, 13, 343-358 343

Complex and Differential Glial Responses in Alzheimers Disease and


Jos J. Rodrguez1,2,*, Arthur M. Butt3, Emanuela Gardenal1,2, Vladimir Parpura4,5 and

Alexei Verkhratsky1,2,6

Achcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011,
Bilbao, Spain; 2Department of Neuroscience, University of the Basque Country UPV/EHU and CI-
BERNED, 48940, Leioa, Spain; 3Institute of Biomedical and Biomolecular Sciences, School of Phar-
macy and Biomedical Sciences, University of Portsmouth, United Kingdom; 4Department of Neurobi- Please provide
ology, Center for Glial Biology in Medicine, Civitan International Research Center, Atomic Force corresponding author(s)
Microscopy & Nanotechnology Laboratories, and Evelyn F. McKnight Brain Institute, University of
Alabama, Birmingham, USA; 5Department of Biotechnology, University or Rijeka, 51000 Rijeka,
Croatia; 6Faculty of Life Sciences, The University of Manchester, Manchester. United Kingdom

Abstract: Glial cells and their association with neurones are fundamental for brain function. The
emergence of complex neurone-glial networks assures rapid information transfer, creating a sophisticated circuitry where
both types of neural cells work in concert, serving different activities. All glial cells, represented by astrocytes, oligoden-
drocytes, microglia and NG2-glia, are essential for brain homeostasis and defence. Thus, glia are key not only for normal
central nervous system (CNS) function, but also to its dysfunction, being directly associated with all forms of neuropa-
thological processes. Therefore, the progression and outcome of neurological and neurodegenerative diseases depend on
glial reactions. In this review, we provide a concise account of recent data obtained from both human material and animal
models demonstrating the pathological involvement of glia in neurodegenerative processes, including Alzheimer's disease
(AD), as well as physiological ageing.
Keywords: Alzheimer's disease, Astrocytes, atrophy, gliosis, microglia, myelin, neurodegeneration, NG2-glia, oligodendro-

1. GLIA IN THE CNS AND THEIR RELEVANCE IN from structural and metabolic support, to information proc-
NEUROLOGICAL AND NEURODEGENERATIVE essing. Thus glia are now considered as key regulatory ele-
PROCESSES ments in morphological and functional plasticity of neural
networks [3, 11-27]. Neuronal-glial connectivity is mediated
In 19th century Rudolf Virchow introduced the concept of
through multiple glial neurotransmitter receptors, which are
neuroglia (defined as Nervwenkitt or nerve cement) as a
specifically concentrated in perisynaptic processes, being an
connective tissue into which all elements of the central nerv-
important functional component of the multipartite synapse
ous system, from neurones to vascular components, are em-
[28-32]. The multipartite synapse comprises the presynaptic
bedded [1-3]. He did not, however, consider its cellular na-
axon terminal, the postsynaptic component (either somata,
ture, although several types of glial cells were described in dendrites or dendritic spines), and astrocytic membranes,
the 19th century [4-8]. Glial cells are classically divided into
enwrapping the former elements, together with additional
macroglia (astrocytes and oligodendrocytes, both of ecto-
components represented by the extracellular matrix and syn-
dermal origin) and microglia (the resident CNS macrophages
aptic processes from NG2-glia and microglia [28, 29].
of myeloid origin). More recently, NG2-glia (also known as
oligodendrocyte precursors or OPs or polydendrocytes) Astrocytes provide for structural and functional isolation
have been identified as a distinct macroglial cell type, which of synaptic inputs and for integration of synaptic activity
represents the largest proliferative cell population within the within the neuronal-glial-vascular unit and astroglial syn-
adult brain, responsible for the life-long generation of oli- cytia [23, 32]. Furthermore, astroglial cells are responsible
godendrocytes [9, 10]. for the delivery of energy substrates through the astroglial-
neuronal-lactate shuttle [18, 32]. This concept has been fur-
In recent decades, the importance and versatility of glia
ther detailed and expanded evolving towards the new con-
has become more fully appreciated, with functions ranging cept of a glial cradle, in which astrocyte processes control
multiple processes from synaptogenesis and synaptic matura-
*Address correspondence to this author at the Achcarro Basque Center for
Neuroscience, IKERBASQUE, Department of Neuroscience, The Univer-
tion to synaptic extinction [29-34]. This versatility of astro-
sity of the Basque Country UPV/EHU. Technological Park, Bldg. 205, cytes is key to the development of human intelligence and to
Floor -1. Laida Bidea. 48170-Zamudio. Vizcaya, Spain; potential alterations of the latter [25, 27, 35].
Tel: +34-946018305; Fax: +34-946018289;

1567-2050/16 $58.00+.00 2016 Bentham Science Publishers

344 Current Alzheimer Research, 2016, Vol. 13, No. 4 Rodrguez et al.

The defence system of the CNS (separated from the rest trodegeneration and astroglial atrophy are central pathologi-
of the body by the blood-brain barrier) is formed and con- cal factors that preceded overt neuronal death and the ap-
trolled by glia, which are highly sensitive and responsive to pearance of clinical symptoms [30-32, 47, 64]. At the later
environmental stress and pathological insults. CNS lesions, stages of the ALS, reactive astrogliosis becomes evident,
regardless of their nature, trigger evolutionarily conserved although the atrophic astrocytes are still present around le-
cascades of glial "damage" responses, generally known as sion sites [50, 67, 68]. Importantly, the silencing of ALS-
reactive gliosis. Glial reactivity is characterized not only by related mutant SOD1 gene in astrocytes delayed the appear-
morphological remodelling [36], but also by functional re- ance of clinical symptoms [30, 31, 69].
modelling [27], depending on the pathological process. As-
Astroglial loss of function represents the primary patho-
trocytes generally undergo reactive astrogliosis [37, 38],
genic event in Wernicke encephalopathy, a substrate for
critical for both sealing the damaged area through scar for- Korsakoff syndrome [70, 71]. The loss of astroglial function
mation (anisomorphic astrogliosis), and for neuroprotection
is manifested by compromised glutamate homeostasis fol-
and post-insult remodelling of neural circuits (isomorphic
lowing down-regulation of astroglial glutamate transporters
astrogliosis) [27, 36]. Oligodendrocytes, on the other hand,
EAAT1 and EAAT2. Failure in glutamate homeostasis insti-
undergo Wallerian degeneration [39, 40], which is closely
gates neuronal excitotoxicity and severe brain lesions charac-
associated with a slow generation of new oligodendrocytes
teristic for the disease [72, 73]. Similarly in Huntingtons
through proliferation and differentiation of NG2-glia cells, to and Parkinsons diseases, loss of astroglial glutamate uptake,
counteract the loss of oligodendrocytes and myelin [9, 10,
an increase in astroglial glutamate, release contribute to neu-
41, 42]. Finally, microglial cells react to CNS damage by a
rodegenerative progression [74-78].
multi-stage and complex process of microglial activation and
active recruitment [30, 31, 43-47], which underlies immune Astrocytes are central elements of Alexanders disease, a
and phagocytic responses of the nervous tissue. rare disorder that arises from mutations in glial fibrillary
acidic protein (GFAP), the major intermediate filament pro-
The complementary orchestration of glial defensive cas-
tein of astrocytes [79]. Although GFAP is expressed at lower
cades defines the progression and outcome of virtually all
levels in a number of cell types throughout the body, evi-
neurological diseases, at both acute and chronic stages [30,
dence points to initial dysfunction of astrocytes as the key
31, 48-51]. Astrocytes are specifically important for the pro-
initiating event that then leads to a cascade of effects, ulti-
gression of acute brain insults, such as trauma and stroke
mately affecting every other cell type in the CNS [80].
[52, 53], as well as for pathophysiology of chronic neuro-
logical disorders [54], such as epilepsy, depression and
schizophrenia, where astrocytes display degenerative and 2. ASTROCYTES IN DEMENTIA AND ALZ-
pathological signs. Astrocytes (both pre-existing and newly
generated through gliogenesis) are actively involved in re- 2.1. Dementia
generation aimed at the restoration of the affected neural
networks as well as the neural-glial-vascular units [49, 55- Astrocytes display pathological changes of both atrophic
58]. Oligodendrocytes are central to diseases of white matter, and reactive nature in various forms of non-AD dementia. In
which accounts for > 50% of the overall brain volume in frontotemporal dementia, astrocytes undergo early apoptotic
humans, and is critical for rapid integrative brain function death and dystrophy [81, 82], which correlates with the se-
through the axonal support and myelination [56-58]. Damage verity of dementia. Post-mortem tissues are heavily popu-
to oligodendroglia are fundamental for demyelinating disor- lated with reactive astrocytes, with up to 5 times increase in
ders, including multiple sclerosis [30, 31, 62-65]. In this re- astrocyte density being detected in some studies [79]. An
spect, NG2-glia are key to white matter pathology, since astrogliotic response was also found in thalamic dementia,
they are responsible for the regeneration of oligodendrocytes where pathological remodelling was specifically observed in
and remyelination, which is essential to recovery and repair perivascular and perineuronal astroglial processes. Both as-
[9, 10]. Microglial cells, as the immune and phagocytic ele- trogliosis and astroglial apoptosis and astrodegeneration
ments of the CNS are, therefore, involved in every type of were detected in immunodeficiency virus-1 (HIV-1) associ-
neuropathology; contributing to associated neuroinflamma- ated dementia (HAD) [30, 31, 83-85], being observed in sub-
tory responses [30, 31, 43, 47, 66]. jects with rapidly progressing cognitive deficits [86].

Neurodegenerative diseases invariably commence from 2.2. Alzheimers Disease

altered synaptic and non-synaptic contacts between neural
cells. This early stage of neurodegeneration is extremely AD appears in both genetic (family Alzheimer's disease
important, because when appropriately tackled, neurodegen- or FAD) and sporadic (SAD) forms [87]. AD is characterised
eration can be arrested or even reversed, thus preventing by progressive neurodegeneration, the histopathological
cognitive decline and even restoring cognitive function. The hallmarks of the disease being (i) focal extracellular deposits
disruption of glial maintenance of synaptic connectivity is a of fibrillar -amyloid (also called neuritic or senile plaques)
key element in the early stages of neurodegenerative proc- in brain parenchyma and in the wall of blood vessels, and (ii)
esses. It is poorly recognised that, in addition to classic glial intraneuronal accumulation of neurofibrillary tangles origi-
reactivity, neurodegeneration is associated with gliodegen- nating from the abnormal hyperphosphorylation of tau fila-
eration, with a corresponding loss of glial function. Astrode- ments [30-32, 88-92]. The initial neurodegenerative events
generation often precedes astrogliosis, the latter being re- in AD appear in the transentorhinal cortex, spreading to the
garded as a general reaction at the later stages of the disease. entorhinal cortex (EC) and hippocampus; at the later stages
In amyotrophic lateral sclerosis (ALS), for example, as- histopathologoical hallmarks disseminate through the tempo-
Glia in Alzheimers Disease and Ageing Current Alzheimer Research, 2016, Vol. 13, No. 4 345

ral, frontal, and parietal lobes [88, 89]. At these late stages, 31, 101, 102]. On the other hand, there are some indications
the grey matter undergoes severe damage manifested by a that astrocytes may accumulate (questionably by phagocyto-
profound loss of neurones and synaptic contacts. sis) and degrade A, thereby reducing A load [90]. For
example, accumulation of A was observed in astrocytes
The role of astrocytes in the pathogenesis and progres-
sion of AD is not yet clear. It is generally agreed that at the from entorhinal cortex of AD patients [103]. In support of
this, astrocytes isolated from healthy brains migrated to-
late stages of the disease (as shown by post-mortem tissues
wards plaques and accumulated A when plated onto brain
analysis) there is a prominent reactive astrogliosis and inclu-
slices isolated from mutant APP transgenic mice. In contrast,
sion of astrocytes and microglial cells into senile plaques
astrocytes isolated from the APP mice were unable to clear
[51, 90, 91]. This pathology was initially identified by Alois
A loads [104]. Similarly, very little (if any) A accumula-
Alzheimer , who described glial cells as an integral part of
the neuritic plaque [92-95] (Fig. 1). tion by reactive astrocytes surrounding plaques was observed
in 3xTg-AD mice [30-32, 91, 105].
Identification of molecules and/or components of AD
These studies suggest the interactions of astrocytes with
pathology that trigger astrogliosis remain to be determined,
A are not straightforward and may depend on their reactive
although several lines of evidence indicate that -amyloid
state. Studies in the 3xTg-AD mouse model demonstrate
peptide (A) by itself seems to be an activating signal. For
example, exposure of primary glial cell cultures to aggregate astrocytes undergo complex pathological changes, depending
on the brain area and stage of the disease, whilst the total
-amyloid or to amyloid plaques isolated from human AD
number of astrocytes remained stable, even up to 24 month
brains induces reactive astrogliosis [96]. Simultaneously, A
in any of the mnesic areas relevant to AD [105, 106]. At the
may trigger astrocytic calcium (Ca2+) signals (represented by
early stages of the disease (i.e. pre-plaque), astrocytes in
both [Ca2+]i transients and [Ca2+]i oscillations) in astroglial-
hippocampus and entorhinal cortex (EC) demonstrate signs
neuronal co-cultures [97]. These Ca2+ oscillations are some-
how involved in A-induced neurotoxicity, probably through of atrophy and degeneration [29, 91, 94, 95, 105, 107, 108]
(Fig. 2). These changes are marked by reduced expression of
the release of reactive oxygen species from A-stimulated
GFAP and decreased number and branching of cell proc-
astrocytes [32, 98]. Abnormal Ca2+ signalling was also ob-
esses, and are field specific in the hippocampus (DG & CA1)
served in vivo, in transgenic AD mouse models, evinced as
and layer specific in the EC (layers II & VI) [29, 91, 94, 95
an anomalous spontaneous Ca2+ wave propagation in astro-
105, 107] (Fig 2). Astroglial atrophy the 3xTg-AD mouse
cytes located in the vicinity of neuritic plaques [99]. A was
also reported to decrease expression and activity of GLAST- followed a specific course through the brain regions, compa-
rable to the neuropathology of human AD, commencing in
and GLT-1 mediated glutamate uptake in cultured astrocytes
the EC (1 month of age), subsequently appearing in the pre-
frontal cortex (PFC, 3 months of age), and finally in the hip-
The question of whether astrocytes participate in produc- pocampus (9 - 12 months of age) [105, 107, 108] (Fig. 2). At
tion/sequestration of A in AD remains debatable. Astro- the later stages of the disease, plaque formation and accumu-
cytes from mice expressing double mutated lation triggers an astrogliotic reaction exclusively in the hip-
Tg(APPSWE)2576Kha (K670N-M671L APP) were reported pocampus and not in the EC or PFC, characterised by
to express -secretase, thus being able to produce A [30,

Fig. (1). (A) Alois Alzheimers drawing illustrating the glial reaction (astrogliosis and hypertrophy) in a pathological brain containing senile
plaques. gaz, neurone; glz, glial cell, P central part of the plaque; P2, peripheral part of the plaque [89]. (B) Photomicrograph showing the
presence of -amyloid within the pyramidal neurones of CA1 as well as the presence of a plaque in 12 months 3xTg-AD mice. (C, E). Con-
focal images of -amyloid (red) and reactive astrocytes (green) associated with senile plaques (C) and diffuse amyloid deposits (D) in the
hippocampus of the 3xTg-AD animal model. Modified and adapted from [92-95].
346 Current Alzheimer Research, 2016, Vol. 13, No. 4 Rodrguez et al.

Fig. (2). Confocal micrographs illustrating GFAP astroglial atrophy in the hippocampal dentate gyrus (DG) and Corni Ammonia 1 (CA1)
regions as well as in the entorhinal cortex (EC) and prefrontal cortex (PFC) in 3xTg-AD mice compared with control animals. Modified and
adapted from [94, 95, 107, 108].

the accumulation of hypertrophic astrocytes around neuritic These differential changes in astrocytes appear to be di-
plaques and -amyloid loaded blood vessels [30-32, 91, 105, rectly associated with the specific vulnerability of different
107, 108] (Figs. 3, 4). In addition, astrocytic glutamate me- brain regions to AD type pathology [26]. Furthermore, early
tabolism was affected in both hippocampus and PFC, but not atrophy of astroglial cells would have important functional
in the EC, as shown by a decrease in GS expression and consequences affecting synaptic coverage and functional
number of anti-GS-immunolabeled astrocytes [106, 109, performance of neuronal-glial-vascular units. Astroglial me-
110] (Fig. 5). diated early imbalance in mnesic areas would clearly affect
Glia in Alzheimers Disease and Ageing Current Alzheimer Research, 2016, Vol. 13, No. 4 347

Fig. (3). (A,B) Confocal images of hippocampal preparations dually labeled by GFAP and by anti- amyloid monoclonal antibody illustrating
differential changes in GFAP profiles in astrocytes distant to the plaques (A) and associated with the Ab plaques (B). (CE) Confocal dual
labelling images (GFAP in green and Ab in red) in 3xTg-AD mice showing the accumulation of astrocytes around the Ab plaques and vascu-
lar Ab deposits. Astrocytes surrounding Ab plaques (D, E) and Ab loaded blood vessel (C), undergo astrogliosis. Modified and adapted from
connectivity in neural networks, reducing synaptic strength hippocampus of 21-month-old rats, the volumes of astrocytes
and disturbing synaptic plasticity, with obvious cognitive labelled with antibodies against glutamine synthetase was ~
consequences [34]. Interestingly, morphological atrophy of 2 times larger that in 5-month- old animals [113]. This astro-
astrocytes in transgenic AD animals can be restored by a cytic change in aged brain was also found to be region-
long-lasting exposure to environmental stimulation, which specific; the GFAP-positive astroglial profiles appear to be
arguably may coincide with certain cognitive improvement significantly increased in the CA1 region and DG of the hip-
[45, 111, 112,] (Fig. 6). pocampus, whereas they are significantly smaller in the EC
[119] (Fig. 7) At the same time, morphological profiles of
2.3. Physiological Ageing astrocytes labelled with anti-S100 antibodies are increased
in the aged DG and EC, but not in the CA1 hippocampal
Two diverging traits in human senescence are clearly dis- region, whereas GS-positive profiles were smaller in the old
tinguishable: the brain may undergo physiological ageing in CA1 and DG, whilst no changes were found in the EC [119].
which adaptive plasticity compensates for age-dependent Astroglial adaptive plasticity can be also mainifested by an
deterioration, or ageing can take a pathological route mani- age-dependent increase in GFAP expression and hypertrophy
fested by neurodegeneration, ultimately leading to dementia of these cells. Hence, physical activity of aged mice and rats
[113, 114]. Age-dependent astroglial remodelling, either or their experience of an enriched environment resulted in an
protective or maladaptive, is an important component for increased GFAP expression in the hippocampus and to astro-
determining this pathophysiological switch. cytic hypertrophy with an elaborated morphological com-
Post-mortem human studies did not find significant plexity [45, 120, 121].
changes in the number of astrocytes when comparing old vs. Age-associated changes in astroglial physiology include
young-adult brains [115, 116]. In old rodents, however, an a decreased expression of ionotropic glutamate and purine
increase [117], a decrease [118] and no change [105, 119, receptors, as wells as decrease in Ca2+ signaling in old ani-
120] in the number of GFAP-positive astroglial cells in the mals (18-21 months) [122]. Expression of aquaporin 4, form-
hippocampus has been reported. Age-dependent changes in ing water channels, was similarly decreased in old astro-
astroglial morphology were also identified. Hence, in the
348 Current Alzheimer Research, 2016, Vol. 13, No. 4 Rodrguez et al.

Fig. (4). -Amyloid depositions trigger gliotic response in associated astrocytes in the hippocampus but not in the entorhinal cortex nor in the
prefrontal cortex. (A, B) Confocal images of hippocampal preparations labeled for glial fibrillary acidic protein (GFAP; green) and -amyloid
(red) illustrating differential changes in GFAP profiles in astrocytes in close association with A plaques (A) and atrophic profiles of astro-
cytes distant from -amyloid deposits (B) in 3xTg-AD mice. (C, D) Confocal dual labeling images (GFAP in Green and -amyloid in red)
showing absence of reactive response of astrocytes in the entorhinal cortex of 3xTg-AD mice around perivascular vascular -amyloid depos-
its (C) and -amyloid plaques (D). (E-F). Confocal images illustrating A aggregates in the mPFC, but few GFAP-positive neighbouring
astrocytes (E and asterisk), and an A loaded blood vessel surrounded by some reactive astrocytes in an 18- month-old 3 Tg-AD ani-
mal (F). Modified and adapted from [107, 108].

cytes, which may contribute to age-dependent deficits in the ticular throughout the cerebral cortex [30, 31, 59, 61]. Pri-
glymphatic system and therefore in protein waste clearance mary and/or secondary oligodendrocyte death and myelin
[123]. There is emerging evidence for astrocytes acquiring a damage occurs in most, if not all, CNS diseases, including
senescence-associated secretory phenotype, characterised by stroke, perinatal ischemia, multiple sclerosis, psychiatric
an increased expression of cytokines and accumulation of disorders, traumatic injury and AD [125].
proteotoxic aggregates [124].
Myelination increases during postnatal development,
peaks at around 45 years and subsequently decreases to in-
3. OLIGODENDROGLIA, MYELIN AND NG2-GLIA fancy levels as age approaches 100 years [126]. The life-long
IN DEMENTIA AND ALZHEIMERS DISEASE generation of new oligodendrocytes and myelin is a function
Oligodendrocytes are the major cell type of CNS white of oligodendrocyte precursors (OPs), also known as NG2-
matter, which in humans represents around 50% of brain glia or polydendrocytes. However, myelin loss is evident
volume, but are also present in the grey matter and in par- with aging in the cerebral cortex, especially in areas related
Glia in Alzheimers Disease and Ageing Current Alzheimer Research, 2016, Vol. 13, No. 4 349

Fig. (5). (A-B) Confocal micrographs showing GFAP (green) and GS (red) labelling in the hippocampus of either control (A) or 3xTg-AD
mice (B). Majority of astrocytes co-express (yellow) GFAP and GS in control mice, whilst some of GFAP positive astrocytes of the 3xTg-AD
mice fail to express GS (arrows). (C-D) Differential distribution and number of GS-IR astrocytes between control (non-TG) and 3xTg-AD
mice. Light micrographs showing the distribution of GS-IR astrocytes within the mPFC in Non-Tg control (C) and 3xTg-AD (D) animals. (E)
Confocal micrographs illustrating GFAP (blue), GS (red) and A (green) labelling. Several GFAP positive astrocytes in surrounding A
plaques (<50m) lack of GS immunoreactivity (1), whilst others co-express GFAP and GS, without the typical extended GS domain (2). (3)
Astrocytes > 50m away from A deposits co-expressing GFAP and GS in their cell bodies and main processes (pink). The distal fine proc-
esses express just GS (red). Modified and adapted from [106, 109, 110].

to cognition and memory, including the frontal lobes (re- mains unclear whether it is secondary to changes in neuronal
viewed in [30, 31, 61, 126]). Thus, intracortical and subcor- function.
tical myelin levels diminish drastically, as observed in both
A key event to oligodendrocyte and myelin pathophysi-
magnetic resonance imaging (MRI) of normal individuals ology is Ca2+ dyshomeostasis, which is caused by aberrant
and in post-mortem studies. The molecular mechanisms
signalling by extracellular molecules, such as neurotransmit-
leading to age-dependent myelin loss have not been eluci-
ters, or alterations in the control of intracellular cytosolic
dated yet and may include oxidative stress, hypoperfusion,
Ca2+ stores. Oligodendrocytes and myelin express ligand-
increased cortisol levels and excitotoxicity, together with
gated channels (including glutamate and ATP receptors) that
neuroinflammation. It is also conceivable that myelin loss
are permeable to Ca2+, and their prolonged activation triggers
can also be due to, or at the least aggravated by, a failure in oligodendrocyte death and myelin destruction, as a conse-
recruiting NG2-glia and a decline in remyelination [42, 127-
quence of cytosolic Ca2+ overload, mitochondrial Ca2+ ac-
130]. Myelin loss would inarguably contribute to neuronal
cumulation, increased production of radical oxygen species,
demise and the decline of brain function in aging, but it re-
350 Current Alzheimer Research, 2016, Vol. 13, No. 4 Rodrguez et al.

Fig. (6). GFAP-immunorectivity of astrocytes in the DG of non-Tg and 3xTg-AD animals housed in different conditions. High magnification
of representative confocal micrographs showing the astrocytic morphology in mice housed in standard conditions (STD), running (RUN), and
enrichment environment (ENR). Note the morphological changes of the astrocytes from both genotypes induced by the different living condi-
tions. Reproduced from [112].

Fig. (7). Representative confocal 3-dimensional reconstructed images showing glial fibrillary acidic protein immunoreactive astrocytes in the
dentate gyrus (DG), cornu ammonis 1 (CA1), and entorhinal cortex (EC) of animals at 3 months (A, E, and I), 9 months (B, F, and J), 18
months (C, G, and K), and 24 months of age (D, H, and L), respectively. Modified and adapted from [119].
Glia in Alzheimers Disease and Ageing Current Alzheimer Research, 2016, Vol. 13, No. 4 351

and release of proapoptotic factors that activate caspases patients [30, 31, 149]. Thus, calmodulin has reduced efficacy
[125, 131]. Glutamate and ATP excitotoxicity constitute an in activating 3',5' cyclic nucleotide phosphodiesterase
important disease mechanism, since these are among the (CNPase), which is exclusively and constitutively expressed
most abundant molecules in brain tissue and acute transient in oligodendrocytes, whereas calbindin has reduced levels in
alterations in their homeostasis as well as chronic pathologi- white matter [30, 31, 149].
cal states can over-activate their receptors and damage oli-
Recent studies have provided more details about the na-
godendroglia and myelin [60, 125]. However, the extent to
ture of the damage to white matter and the type of non-
which excitotoxicity contributes directly to demyelination in Alzheimer dementia. Thus, patients with frontotemporal de-
aging and dementia is not known.
mentia show ischemic-like primary incomplete infarction of
In parallel, there is evidence that NG2-glia need gluta- frontal white matter, which shows gliosis and demyelination
mate signalling for myelination through the synapses they [30, 31, 150], and those with ALS-related dementia display
form with the neighbour neurons and axons [132-136]. NG2- diffuse fibrous gliosis in frontotemporal white matter [151].
glia proliferate and migrate via AMPA receptor activation, In turn, depressed patients with mild non-Alzheimer demen-
whilst the signal for myelination arrives via NMDA recep- tia have changes in white matter MRI hyperintensity vol-
tors [135, 137-139]. The AMPA and NMDA receptors are umes [152], a feature that also occurs in vascular dementia
expressed in mature oligodendrocyte somata and myelin, [153]. Importantly, these changes in hyperintensity have
respectively [132, 140], and this has led to the hypothesis predictive value for the onset and progression of dementia
that communication between axons and myelin represents a [152, 153].
new type of axon-myelin synapse [141]. After demyelina-
tion, the formation of neuron-NG2-glia synapses suggests 3.2. Alzheimers Disease
that synaptic glutamate signalling is important for the early
stages of remyelination [142]. Thus, myelina- It is well known that white matter is altered in AD. White
tion/remyelination is dependent on axonal activity and glu- matter alteration in specific areas of the brain during the pro-
tamatergic signalling even in adulthood [42]. gression of AD appears to impair cognitive functions that
rely on networks involving those regions, and the extent of
this damage is associated with dementia severity in AD
3.1. Ageing and Dementia
[154]. A high percentage of AD patients exhibit evidence of
The effects of age on oligodendrocytes and myelin have white matter degeneration with severe loss of oligodendro-
been recently examined experimentally in the primary visual cytes by apoptosis [125, 155]. Despite the fact that the
cortices of rhesus monkeys that had been also behaviourally mechanisms underlying this damage are not well understood,
tested [143]. Alterations in myelin sheaths increase with age it is clear that they involve both, amyloidoisis and Ca2+ dy-
being an age-related increase in the frequency of profiles of shomeostasis [125, 156].
nerve fibres sectioned through paranodes, indicating that -amyloid peptides can damage oligodendrocytes in vitro
shorter lengths of myelin are being produced by remyelina-
[157] and increase their vulnerability to glutamate toxicity
tion. In addition, alterations in myelin correlate with the
[125, 158]. Injection of amyloid 1-42 into white matter
number of oligodendrocytes, suggesting that with age newly
causes axon disruption and myelin damage, as well as oli-
generated oligodendrocytes are required to remyelinate nerve
godendrocyte loss and profound gliosis [125, 159]. In the
fibres. For this of course is needed an active presence and
presenilin-1 mutant knock-in mice are more susceptible to
proliferation of NG2-glia, which in an equivalent manner glutamate excitotoxicity and exhibit an abnormality in Ca2+
also decreases the rate of self renewal with age [9, 125, 144,
regulation, which is responsible for their demise [158].
Moreover, when exposed to the demyelinating agent cupri-
These data suggest that structural integrity of myelin zone, this model exhibit enhanced white matter damage and
sheaths deteriorates during ageing and leads to impaired effi- learning and memory deficits compared to wild-type mice
ciency in information flow along neural networks and thus to [125, 158]. Thus, specific presenilin-1 mutation in oligoden-
cognitive decline. This is supported by MRI studies of the drocytes has detrimental effects leading to disease, and indi-
human corpus callosum indicating breakdown of white mat- cate that white matter damage may well contribute to cogni-
ter structural integrity in ageing [30, 31, 146] and a 20% tive dysfunction in AD.
decrease in the number of myelinated nerve fibres in the cor-
In 3xTg-AD mice, significant region-specific alterations
pus callosum and fibre tracts associated with frontal lobe
in myelination patterns and in oligodendrocyte marker ex-
areas in ageing monkeys [125, 147]. Moreover, these obser- pression profiles were observed at time points preceding the
vations imply that inter-hemispheric connectivity of the fron-
appearance of amyloid and tau pathology [30, 31, 160].
tal lobes is most severely affected and, consequently, mal-
These findings indicate that myelin and oligodendrocyte
function of cognition-related areas [146].
defects in AD occur before the onset of symptoms and may
Early MRI studies of patients with non-Alzheimer de- be key players in the development of this disease. Indeed,
mentia have also shown diffuse, patchy white matter lesions lesions are prevalent in early-stage AD, in periventricular
in all cases examined [148]. The grade of severity of the and deep white matter [30, 31,161]. Notably, the burden of
changes and the prevalence observed was higher than in both types of lesions is associated with reduced global cogni-
cognitively normal subjects. Interestingly, calcium binding tion, as assessed by evaluating visual memory, processing
proteins calmodulin and calbindin have altered expression speed and executive function.
and function in the white matter of non-Alzheimer dementia
352 Current Alzheimer Research, 2016, Vol. 13, No. 4 Rodrguez et al.

In addition, we have detected marked changes in NG2- Microglial activation in AD brains has multiple origins
glia in 3xTg-AD mice, throughout the full extension of the and nature, including amyloid peptides, APP and different
hippocampus, as shown by an evident atrophy at early stages molecules released by damaged neurones and activated as-
of the disease, before the presence of A plaques [63]. NG2- trocytes [167, 168]; whether it is soluble A or consolidated
glia in age-matched non-Tg mice have a characteristic multi- plaques, which act as the ultimate activating signal remains
processed morphology and often appear as duplets or trip- unclear [48]. Recent studies using in vivo multiphoton mi-
lets, indicating recent division, which was significantly de- croscopy on 5 - 6 month old B6C3-YFP transgenic mice
creased in 3xTg-AD mice [42]. Note that NG2-glia divide (harbouring APPswe and PS1d9x-YFP genes) demonstrated
asymmetrically to form sister NG2-glia, one for self- that microglia are activated and recruited to A plaques only
renewal and the other differentiates into an oligodendrocyte. after they have been formed [169]. In contrast, in APP V717I
The decrease in sister NG2-glia in 3xTg-AD mice correlated transgenic mice, microglial activation was observed at 3
with retraction of their processes, implying a loss of NG2- months of age, whilst plaques only appear at ~ 10 - 12
glial cell synaptic connectivity may be linked to reduced months of age [102].
regenerative capacity of NG2-glia and myelin loss. At later
Microglial activation by A and senile plaques may in-
stages, when the pathological burden is high, in the 24-
volve multiple receptors and signalling cascades. For exam-
month 3xTg-AD brain and hippocampus, NG2-glia are hy-
ple, AD-associated activation of microglia requires P2X 7
pertrophic and intimately associated with A plaques, which purinoceptors and Ca2+ signalling [30-31, 170]. The role of
appear to be circumscribed by NG2-glia and infiltrated by
P2X7 receptors was specifically highlighted by recent ex-
their processes. This is consistent with changes in NG2-glia
periments in which intra-hippocampal injection of A1-42
in human AD [162]. These studies indicate that atrophy of
failed to induce microglial activation in animals deficient in
NG2-glia is an early feature of AD, concomitant with myelin
P2X7 receptors [30-31, 170]. Microglial activation in AD
loss and synaptic dysfunction, whereas at later stages NG2-
also involves Toll-like receptors of TLR4 and TLR2 type
glia contribute with astrocytes to the inhibitory environment [171, 172]. These receptors are up-regulated in AD animal
of the glial scar in response to patent neuropathology.
models and in post-mortem AD brains [172]. Incidentally, a
spontaneous loss-of-function mutation in the TLR4 gene
3.3. Relevance of Oligodendrocyte and Myelin to Demen- markedly decreased microglial activation induced by A [31,
tia and AD 32, 173, 174].
White and grey matter oligodendrocytes and their precur- The longitudinal AD-induced reactions of microglia are
sors NG2-glia are key cells for information flow in myeli- complex. In 3xTg-AD mice, we have found a substantial
nated axons. Cognitive deficits associated with AD and non- increase in the density of resting (tomato-lectin positive)
AD dementia are paralleled by alterations in myelin patterns. microglia at both early (i.e. pre-plaque) and late stages of the
Furthermore, the myelin sheath is not just an inert insulating disease [44]. At 9 month of age (when the senile plaques are
structure and is essential for the long-term integrity of mye- virtually absent), the density of resting microglia in the hip-
linated axons [23, 27, 42, 132, 133]. Hence, rescuing the loss pocampus of 3xTg-AD was ~105% larger than in control
of myelin is an important target for protecting against irre- mice. This increased density of resting microglia remains at
versible neurodegenerative changes. Moreover, recent stud- older ages (at 12 months it was 54% higher and at 18 month
ies provide evidence that neuron-NG2-glial cell interactions 131% higher compared to the controls). The appearance of
are important for synaptic function and integrity in dementia- plaques triggered microglial activation [44-46, 107, 108].
relevant brain regions [23, 27, 42, 132, 133]. For example, (Fig. 4B); we observed a significant increase in the density
ablation of NG2-glia in the prefrontal cortex of the adult of activated microglia in CA1 hippocampal area of 3xTg-AD
brain causes deficits in excitatory glutamatergic neurotrans- mice at 12 and 18 months, which correlated with the age of
mission and induces depressive-like behaviour in mice [23, the appearance and development of A plaques [44-46] (Fig.
27, 42, 132, 133]. Consequently, novel, effective oligo- and 8). The early increase in the density of resting microglia may
myelin-protective strategies ought to be developed to treat represent the generalized response of the brain defence sys-
more efficiently these disorders. A feasible approach is to tem to the developing AD pathology.
explore the therapeutic potential of specific drugs aiming at
restoring Ca2+ homeostasis. Increased densities of resting and activated microglia in
the dentate gyrus follow senile plaque formation in the CA1
4. MICROGLIA IN DEMENTIA AND ALZHEIMERS subfield of the hippocampus, which is consistent with the
DISEASE later involvement of DG in the human pathology [42, 167].
Compared to non-Tg controls, 3xTg-AD mice displayed a
Neuroinflammation contributes to physiological and significant increase in resting (by 75%) and activated (by
pathophysiological aging, including AD. Activation of mi- 67%) microglia in the molecular layer of the DG at 18
croglia occurs simultaneously with the formation of neuritic months of age [44-46] (Fig. 8F-G). These results indicate a
plaques [51, 163]. Microglial cells together with astrocytes complex microglial remodelling during AD progression and
are closely associated with senile plaques, and they fuel the a specific order of progress within the hippocampal circuitry,
neuroinflammatory process by secreting multiple pro- reacting first in CA1 followed by the DG.
inflammatory factors [164]. Furthermore, activated micro-
Psychostimulation, such as running (RUN) and enriched
glial cells phagocytose -amyloid, thus reducing its load
environment (ENR), prevented this global microglial hippo-
[165, 166].
campal increase observed during the progression of AD in
the 3xTg-AD mice [46]. In the ENR environment a 10%
Glia in Alzheimers Disease and Ageing Current Alzheimer Research, 2016, Vol. 13, No. 4 353

Fig. (8). (A-B) Drawings of Po del Ro-Hortega showing the morphological differences between resting and activated microglial cells in the
rodent brain. (C-D) Visualization and quantification of resting and activated microglia in the hippocampi of 3xTg-AD animals. (C) Bright-
field micrographs of typical resting TL-IR microglia with small cell body showing thin to medium ramified processes extending to the sur-
rounding neuropil in the CA1 subfield, which is not modified either by age or by A amyloid plaques. (D) Fluorescence micrograph illustrat-
ing the characteristic morphology of reactive microglia within the CA1 subfield of the hippocampus of an 18-month-old 3xTg-AD mouse.
Reactive microglia appear with most enlarged cell bodies from which a greater number of numerous processes emanated, but with an en-
larged and thicker appearance. (E). Confocal image showing recruitment of MAC-1- IR microglia (green) in the vicinity of A amyloid ag-
gregates (red) in the CA1 subfield of the hippocampus of an 18-month-old 3xTg-AD mouse. (F-H) Confocal micrographs showing environ-
mental-induced changes in microglial morphology in 3xTg-AD mice housed in STD (F), RUN (G) and ENR (H) environments. Modified
and adapted from [44-46].

reduction in microglial number was detected. A further mor- surface, volume and somata volume (61%, 78% 41 %, re-
phological analysis revealed no changes in microglial cells in spectively) [46]. These results indicate that exposure to RUN
the ENR animals, whereas cell size increased in animals ex- and ENR have differential effects on activation-associated
posed to RUN, due to pronounced increases in microglia changes in microglia in AD pathological states.
354 Current Alzheimer Research, 2016, Vol. 13, No. 4 Rodrguez et al.

5. FINAL REMARKS [5] Andriezen, WL. 1893. The neuroglia elements of the brain. Brit
Med J 2: 227- 230 (1889).
All glial cells types contribute to the progression of Alz- [6] v Lenhossek, M. (1893) Der feinere Bau des Nervensystems im
heimer's disease and ageing. The early AD astrocytic atrophy Lichte neuester Forschung, Fischers Medicinische Buchhandlung
reduces synaptic coverage and support, leading thus to H. Kornfield
weakening of synaptic connectivity associated with early [7] Retzius G. (18941916) Biol Untersuchungen. Die Neuroglia des
Gehirns beim Menschen und bei Saeugethieren, Verlag von Gustav
cognitive deficits. Formation of -amyloid plaques induces Fischer
reactive astrogliosis exclusively in the hippocampus but not [8] Golgi C. (1903) Opera Omnia. Hoepli
in cortical areas; reactive astrocytes are specifically associ- [9] Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A,
ated with -amyloid plaques. Reactive astrocytes contribute et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes
not only to neurotoxicity but also to neuroinflammation, and piriform projection neurons in adult mice. Nat Neurosci 11:
through the release of pro-inflammatory factors and neuro- 1392-401 (2008).
[10] Richardson WD, Young KM, Tripathi RB, McKenzie I. NG2-glia
toxic agents. Atrophy and degeneration of oligodendrocytes as multipotent neural stem cells: fact or fantasy? Neuron 70: 661-
results in white matter shrinkage, contributing to cognitive 73 (2011).
decline and neurodegeneration. Altered regenerative capacity [11] Newman EA, Frambach DA, Odette LL. Control of extracellular
of NG2-glia (OPs) will contribute to myelin loss in ageing potassium levels by retinal glial cell K+ siphoning. Science 225:
and this may be accelerated in AD. Finally, early recruitment 1174-1175 (1984).
of ramified microglia and microglia activation at later stages [12] Verkhratsky A, Kettenmann H. Calcium signalling in glial cells.
Trends Neurosci 19: 346-52 (1996)
initiates and sustains the neuroinflammatory process that
[13] Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes:
results in cell death and brain atrophy. redefining the functional aschitecture of the brain. Trends Neurosci
26: 523-30 (2003).
DISCLOSURE [14] Zonta, M. Angulo, MC. Gobbo, S. et al. Neuron-to-astrocyte sig-
naling is central to the dynamic control of brain microcirculation.
"Part of this article has been reproduced from author pre- Nat Neurosci 6: 43-50 (2003).
vious publication entitled "Neuroglia in Alzheimer's Dis- [15] Simard M, Nedergaard M, The neurobiology of glia in the context
ease" published in Frontiers in Neuroscience, in Astrocytes: of water and ion homeostasis. Neuroscience 129: 877-896 (2004).
Wiring the brain. Eds. Scemes and Spray. Taylor and Fran- [16] Kettenmann, H. Ransom, BR. (eds.) Neuroglia, 3rd Edition (OUP,
Oxford, 2013)
cis, CRC Press. Pages 311-338."
[17] Volterra A, Meldolesi J. Astrocytes, from brain glue to communi-
cation elements: the revolution continues. Nat Rev Neurosci 6:
[18] Magistretti PJ. Neuron-glia metabolic coupling and plasticity. J
The author(s) confirm that this article content has no con- Exp Biol 209: 2304-2311 (2006).
flict of interest. [19] Verkhratsky A. Glial calcium signalling in physiology and patho-
physiology. Acta Pharmacol Sin 27: 773-80 (2006a).
ACKNOWLEDGEMENTS [20] Verkhratsky A. Patching the glia reveals the functional organisa-
tion of the brain. Pflugers Arch 453: 411-20 (2006b).
We thank Drs. Chia-Yu Yeh, Magdalena Kulijewicz- [21] Verkhratsky A, Toescu EC. Neuronal-glial networks as substrate
Nawrot, Markel Olabarria and Harun N. Noristani, for their for CNS integration. J Cell Mol Med 10: 826-36 (2006).
help and assistance in the figures. Authors research was sup- [22] Iadecola C, Nedergaard M. Glial regulation of the cerebral
microvasculature. Nat Neurosci 10: 1369-1376 (2007).
ported by Alzheimers Research Trust (UK) Programme [23] Verkhratsky A, Butt A. Glial Neurobiology. A textbook. John
Grant (ART/PG2004A/1) to AV and JJR; by National Insti- Wiley & Sons, Chichester (2007).
tute of Health (NIH) grant to AV; by the Grant Agency of [24] Verkhratsky A, Kirchhoff F. NMDA Receptors in glia. Neuroscien-
the Czech Republic (GACR 309/09/1696) to JJR and tist 13: 28-37 (2007).
(GACR 305/08/1381 and GACR 305/08/1384) to AV as well [25] Verkhratsky A. Neuronismo y reticulismo: neuronal-glial circuits
as by the Spanish Government,Plan Nacional de I+D+I unify the reticular and neuronal theories of brain organization. Acta
Physiol (Oxf), 195: 111-122 (2009).
2008-2011, and ISCIII SubdireccinGeneral de Evaluacin y
[26] Verkhratsky A. Physiology of neuronal-glial networking. Neuro-
Fomento de la investigacin co-financed by FEDER chem Int 57: 332-43 (2010).
(PI10/02738) to JJR and AV, and the Government of the [27] Verkhratsky A. Butt, A. 2013 Physiology and Pathophysiology of
Basque Country grants (AE-2010-1-28; AEGV10/16, Neuroglia (Wiley, Chichester).
GV2011111020) to JJR; and BBSRC grant to AB [28] Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite syn-
(BB/M029379/1). apses: glia, the unacknowledged partner. Trends Neurosci 22: 208-
215 (1999).
[29] Verkhratsky A, Nedergaard M. Astroglial cradle in the life of the
REFERENCES synapse. Philosophical transactions of the Royal Society of London
[1] Virchow, R. (1856) Gesammelte Abbildung zur wissenschaftlichen Series B, Biol Sci 369: 20130595 (2014).
Medizin, Verlag von Meidinger Sohn & Comp [30] Rodrguez JJ, Matute C, Verkhratsky A. (2012) Neuroglia in Alz-
[2] Virchow, R. (1858) Die Cellularpathologie in ihrer Begrndung auf heimers disease, in Astrocytes: Wiring the brain. Eds. Scemes and
physiologische and pathologische Gewebelehre. Zwanzig Vorle- Spray. Taylor and Francis, CRC Press. Pages 311-338.
sungen gehalten whrend der Monate Februar, Mrz und April [31] Verkhratsky A, Parpura V, Rodrguez JJ. (2014) Neurodegenera-
1858 im pathologischen Institut zu Berlin, August Hirschwald tion and neuroglia: Emphasis on astroglia in Alzheimer's disease,
[3] KettenmannH, Verkhratsky A. Neuroglia: the 150 years after. in Pathological potential of neuroglia: Possible new targets for
Trends Neurosci 31: 653-659 (2008). medical intervention. Eds. Vladimir Parpura and Alexei Verk-
[4] Klliker A. Handbuch der Gewebelehre des Menschen, Wilhelm hratsky. Springer. Pages 265-291.
Engelmann [32] Verkhratsky A, Marutle A, Rodrguez-Arellano JJ, Nordberg A.
Glial asthenia and functional paralysis: A new perspective on neu-
rodegeneration and Alzheimer's disease. The Neuroscientist (2014).
Glia in Alzheimers Disease and Ageing Current Alzheimer Research, 2016, Vol. 13, No. 4 355

[33] Nedergaard M, Verkhratsky A. Artifact versus reality - How astro- [58] Jabs R, Seifert G. Steinhauser, C. Astrocytic function and its altera-
cytes contribute to synaptic events? Glia 60: 1013-23 (2012). tion in the epileptic brain. Epilepsia 49(2): 3-12 (2008).
[34] Rodriguez JJ, Verkhratsky A. Neuroglial roots of neurodegenera- [59] Fields RD. White matter in learning, cognition and psychiatric
tive diseases? Mol Neurobiol 43: 87-96 (2011). disorders. Trends Neurosci 31: 361-370 (2008).
[35] Oberheim NA, Takano T, Han X, He W, Lin JH, Wang F, et al. [60] Matute C, Alberdi E, Domercq M, Sanchez-Gomez MV, Perez-
Uniquely hominid features of adult human astrocytes. J. Neurosci Samartin A, Rodriguez-Antiguedad A, et al. Excitotoxic damage to
29: 3276-87 (2009). white matter. J Anat 210: 693-702 (2007).
[36] Toledano A, lvarez MI, Toledano-Daz A, Merino JJ, Rodrguez [61] Matute C. P2X7 receptors in oligodendrocytes: a novel target for
JJ. Brain local and regional neuroglial alterations in Alzheimers neuroprotection. Mol Neurobiol 38: 123-128 (2008).
Disease: cell types, responses and implications. Curr Alzheimer [62] Antel J, Arnold D. Multiple sclerosis. In Kettenmann, H. Ransom,
Res 13 (2016). B. (eds) Neuroglia. Oxford University Press, Oxford, pp. 489 - 500
[37] Pekny M, Nilsson M. Astrocyte activation and reactive gliosis. Glia (2005).
50: 427-434 (2005). [63] Ercolini AM, Miller SD. Mechanisms of immunopathology in
[38] Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo murine models of central nervous system demyelinating disease. J
AC, et al. Protective role of reactive astrocytes in brain ischemia. J Immunol 176: 3293-3298 (2006).
Cereb Blood Flow Metab 28: 468-481 (2008). [64] Jessen KR, Mirsky R. Negative regulation of myelination: rele-
[39] Koeppen AH. Wallerian degeneration: history and clinical signifi- vance for development, injury, and demyelinating disease. Glia 56:
cance. J Neurol Sci 220: 115-117 (2004). 1552-1565 (2008).
[40] Vargas ME, Barres BA. Why is Wallerian degeneration in the CNS [65] van der Valk P, Amor S. Preactive lesions in multiple sclerosis.
so slow? Annu Rev Neurosci 30: 153-179 (2007). Curr Opin Neurol 22: 207-213 (2009).
[41] Guo F, Maeda Y, Ma J, Delgado M, Sohn J, Miers L, et al. Mac- [66] Ransohoff RM, Perry VH. Microglial physiology: unique stimuli,
roglial plasticity and the origins of reactive astroglia in experimen- specialized responses. Annu Rev Immunol 27: 119-145 (2009).
tal autoimmune encephalomyelitis. J Neurosci 31: 11914-28 [67] Rossi D, Brambilla L,Valori CF, Roncoroni C, Crugnola A, Yo-
(2011). kota, T. et al. Focal degeneration of astrocytes in amyotrophic lat-
[42] Vanzuli I, Rivera A, Arellano JJ, Butt A. Decreased regenerative eral sclerosis. Cell Death Differ 15: 1691-1700 (2008).
capacity of oligodendrocyte progenitor cells (NG2-glia) in the age- [68] McGeer PL, McGeer EG. Inflammatory processes in amyotrophic
ing brain: a vicious cycle of synaptic dysfunction, myelin loss and lateral sclerosis. Muscle Nerve 26: 459-470 (2002).
neuronal disruption? Curr Alzheimer Res 13 (2016) [69] Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita
[43] Hanisch UK, Kettenmann H. Microglia: active sensor and versatile H, Gutmann DH, et al. Astrocytes as determinants of disease pro-
effector cells in the normal and pathologic brain. Nat Neurosci 10: gression in inherited amyotrophic lateral sclerosis. Nat Neurosci
1387-1394 (2007). 11: 251-253 (2008).
[44] Rodrguez JJ, Witton J, Olabarria M, Noristani HN, Verkhratsky A. [70] Korsakoff SS & . (1889).
Increase in the density of resting microglia precedes neuritic (psycho-
plaques formation and microglial activation in a transgenic model sis polineuritica, s. cerebropathia psychica toxaemica). English
of Alzheimers disease. Cell Death & Disease 1: e1 (2010). translation: Korsakoff, S. S. Psychic disorder in conjunction with
[45] Rodrguez JJ, Noristani HN, Hilditch T, Olabarria M, Yeh CY, multiple neuritis, Translated from Russian by Victor, M. and
Witton, J, et al. Increased densities of resting and activated micro- Yakovlev, Neurology (1955), 5: 394 - 406. 32, 3-18.
glia in the dentate gyrus follow senile plaque formation in the CA1 [71] Wernicke C. (1881 - 1883). Lehrbuch der Gehirnkrankheiten fr
subfield of the hippocampus in the triple transgenic model of Alz- Aerzte und Studirende. Theodor Fischer, Kassel und Berlin.
heimer's disease. Neurosci Lett 552: 129-34 (2013). [72] Hazell AS. Astrocytes are a major target in thiamine deficiency and
[46] Rodrguez JJ, Noristani HN, Verkhratsky A. Microglial response to Wernicke's encephalopathy. Neurochem Int 55: 129-135 (2009).
Alzheimer's disease is differentially modulated by voluntary wheel [73] Hazell AS, Sheedy D, Oanea R, Aghourian M, Sun, S. Jung JY, et
running and enriched environments. Brain Struct Funct 220: 941- al. Loss of astrocytic glutamate transporters in Wernicke encepha-
953 (2015). lopathy. Glia 58: 148-156 (2009).
[47] Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology [74] Behrens PF, Franz P, Woodman B, Lindenberg
of microglia. Physiol Rev 91: 461-553 (2011). KS. Landwehrmeyer, GB. Impaired glutamate transport and gluta-
[48] Giaume C, Kirchhoff F, Matute C, Reichenbach A, Verkhratsky A. mate-glutamine cycling: downstream effects of theHunting-
Glia: the fulcrum of brain diseases. Cell Death Differ 14: 1324- ton mutation. Brain 125: 1908-22 (2002).
1335 (2007). [75] Lee W, Reyes RC, Gottipati MK, Lewis K, Lesort M, Parpura V,
[49] Halassa MM, Fellin T, Haydon PG. The tripartite synapse: roles for et al. Enhanced Ca(2+)-dependent glutamate release from astro-
gliotransmission in health and disease. Trends Mol Med 13: 54-63 cytes of the BACHD Huntington's disease mouse model. Neurobiol
(2007). Dis 58: 192-9 (2013).
[50] Rossi D, Volterra A. Astrocytic dysfunction: Insights on the role in [76] Mena MA, Casarejos MJ, Carazo A, Paino CL, Garcia de Ye-
neurodegeneration. Brain Res Bull 80: 224-232 (2009). benes, J. Glia conditioned medium protects fetal rat midbrain neu-
[51] Heneka MT, Rodriguez JJ, Verkhratsky A. Neuroglia in neurode- rones in culture from L-DOPA toxicity. Neuroreport 7: 441-445
generation. Brain Res Rev 63: 189-211 (2010). (1996).
[52] Nedergaard M, Dirnagl U. Role of glial cells in cerebral ischemia. [77] Mena MA, de Bernardo S, Casarejos MJ, Canals S, Rodriguez-
Glia 50: 281-286 (2005). Martin, E. The role of astroglia on the survival of dopamine neu-
[53] Nedergaard M, Rodriguez JJ, Verkhratsky, A. Glial calcium and rons. Mol Neurobiol 25: 245-263 (2002).
diseases of the nervous system. Cell Calcium 47: 140-149 (2010). [78] Mena MA, Garcia de Yebenes J. Glial cells as players in parkin-
[54] Verkhratsky A, Sofroniew MV, Messing A, deLanerolle NC, sonism: the "good," the "bad," and the "mysterious" glia. Neurosci-
Rempe D, Rodrguez JJ, et al. Neurological diseases as primary entist 14: 544-560 (2008).
gliopathies: a reassessment of neurocentrism. ASN Neuro 4(3) [79] Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D,
(2012). Goldman JE. Messing, A. Mutations in GFAP, encoding glial fi-
[55] Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, brillary acidic protein, are associated with Alexander disease. Nat
Meltzer HY, et al. Morphometric evidence for neuronal and glial Genet 27: 117-120 (2001).
prefrontal cell pathology in major depression. Biol Psychiatry 45: [80] Brenner M, Goldman JE, Quinlan RA, Messing A. Alexander
1085-1098 (1999). disease: a genetic disorder of astrocytes. In Parpura, V. Haydon,
[56] Tsai G, Coyle JT. Glutamatergic mechanisms in schizophrenia. PG. (eds) Astrocytes in (Patho)Physiology of the Nervous System.
Annu Rev Pharmacol Toxicol 42: 165-179 (2002). Springer, New York, pp. 591-648 (2009).
[57] Tian GF, Azmi H, Takano T, Xu Q, Peng W, Lin, J, et al. An
astrocytic basis of epilepsy. Nat Med 11: 973-981 (2005).
356 Current Alzheimer Research, 2016, Vol. 13, No. 4 Rodrguez et al.

[81] Broe M, Kril J, Halliday GM. Astrocytic degeneration relates to the tivation and precedes amyloid plaque deposition in APP[V717I]
severity of disease in frontotemporal dementia. Brain 127: 2214- transgenic mice. J Neuroinflam 2: 22 (2005).
2220 (2004) [103] Nagele RG, D'Andrea MR, Lee H, 42 and give rise
[82] Kersaitis C, Halliday GM, Kril JJ. Regional and cellular pathology toVenkataraman V, Wang HY. Astrocytes accumulate A astro-
in frontotemporal dementia: relationship to stage of disease in cases cytic amyloid plaques in Alzheimer disease brains. Brain Res 971:
with and without Pick bodies. Acta Neuropathol 108: 515-523 197-209 (2003).
(2004). [104] Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et
[83] Potts R, Leech RW. Thalamic dementia: an example of primary al. in vitro and in situ. Nat Med 9:Adult mouse astrocytes de-
astroglial dystrophy of Seitelberger. Clin Neuropathol 24: 271-275 grade amyloid- 453-457 (2003).
(2005). [105] Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ. Con-
[84] Kaul, M. Garden, GA. Lipton, SA. Pathways to neuronal injury and comitant astroglial atrophy and astrogliosis in a triple transgenic
apoptosis in HIV-associated dementia. Nature 410: 988-994 animal model of Alzheimer's disease. Glia 58: 831-838 (2010).
(2001). [106] Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ. Age-
[85] Vanzani MC, Iacono RF, Caccuri RL, Troncoso AR, Berria MI. dependent decrease in glutamine synthetase expression in the hip-
Regional differences in astrocyte activation in HIV-associated de- pocampal astroglia of the triple transgenic Alzheimer's disease
mentia. Medicina (B Aires), 66: 108-112 (2006). mouse model: mechanism for deficient glutamatergic transmission?
[86] Thompson KA, McArthur JC. Wesselingh, SL. Correlation be- Mol Neurodegener 6: 55 (2011).
tween neurological progression and astrocyte apoptosis in HIV- [107] Yeh CY, Vadhwana B, Verkhratsky A, Rodriguez JJ. Early astro-
associated dementia. Ann Neurol 49: 745-752 (2001). cytic atrophy in the entorhinal cortex of a triple transgenic animal
[87] Alzheimer A. ber eine eigenartige Erkrankung der Hirnrinde. model of Alzheimer's disease. ASN Neuro 3: 271-279 (2011).
Allg. Z. Psychiat. Psych.-Gericht Med 64: 146-148 (1907). [108] Kulijewicz-Nawrot M, Verkhratsky A, Chvatal A, Sykova E,
[88] Thompson PM, Hayashi KM, de Zubicaray G, Janke AL, Rose SE, Rodriguez JJ. Astrocytic cytoskeletal atrophy in the medial pre-
Semple J, et al. Dynamics of gray matter loss in Alzheimer's dis- frontal cortex of a triple transgenic mouse model of Alzheimer's
ease. J Neurosci 23: 994-1005 (2003). disease. J Anatomy 221: 252-262 (2012).
[89] Thompson PM, Hayashi KM, Dutton RA, Chiang MC, Leow AD, [109] Kulijewicz-Nawrot M, Sykov E, Chvtal A, Verkhratsky A, Ro-
Sowell ER. et al. Tracking Alzheimer's disease. Ann NY Acad Sci drguez JJ. Astrocytes and glutamate homoeostasis in Alzheimer's
1097: 183-214 (2007). disease: a decrease in glutamine synthetase, but not in glutamate
[90] Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC. Con- transporter-1, in the prefrontal cortex. ASN Neuro 5: 273-82 (2013)
tribution of glial cells to the development of amyloid plaques in [110] Yeh CY, Verkhratsky A, Terzieva S, Rodrguez, JJ. Glutamine
Alzheimer's disease. Neurobiol Aging 25: 663-674 (2004). synthetase in astrocytes from entorhinal cortex of the triple trans-
[91] Rodriguez JJ, Olabarria M, Chvatal A, Verkhratsky A. Astroglia in genic animal model of Alzheimer's disease is not affected by patho-
dementia and Alzheimer's disease. Cell Death Differ 16: 378-385 logical progression. Biogerontology 14: 777-87 (2013).
(2009). [111] Beauquis J, Pava P, Pomilio C, Vinuesa A, Podlutskaya N, Galvan
[92] Alzheimer A. Beitrge zur Kenntnis der pathologischen Neuroglia V, et al. Environmental enrichment prevents astroglial pathological
und ihrer Beziehungen zu den Abbauvorgngen im Nervengewebe. changes in the hippocampus of APP transgenic mice, model of
In Nissl, F., Alzheimer, A. (eds) Histologische und histopatholo- Alzheimer's disease. Exp Neurol 239: 28-37 (2013).
gische Arbeiten ber die Grosshirnrinde mit besonderer Bercksi- [112] Rodrguez JJ, Terzieva S, Olabarria M, Lanza RG, Verkhratsky A.
chtigung der pathologischen Anatomie der Geisteskrankheiten. Enriched environment and physical activity reverse astrogliodegen-
Gustav Fischer, Jena, pp. 401-562 (1910). eration in the hippocampus of AD transgenic mice. Cell Death Dis
[93] Rodrguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, et al. 4(6): e678 (2013).
Impaired adult neurogenesis in the dentate gyrus of a triple trans- [113] Toescu EC, Verkhratsky A. Landfield, PW. Ca2+ regulation and
genic mouse model of Alzheimer's disease. PLoSOne 3(8): e2935 gene expression in normal brain aging. Trends Neurosci 27: 614-
(2008). 620(2004).
[94] Rodrguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A. Astro- [114] Burke SN, Barnes CA. Neural plasticity in the ageing brain. Nat
cytes in physiological aging and Alzheimer's disease. Neurosci- Rev Neurosci 7: 30-40 (2006).
ence pii: S0306-4522(15)00031-7 (2015). [115] Fabricius K, Jacobsen JS, Pakkenberg B. Effect of age on neocorti-
[95] Verkhratsky A, Zorec R, Rodrguez JJ, Parpura V. Astroglia dy- cal brain cells in 90+ year old human females a cell counting
namics in ageing and Alzheimer's disease. Curr Opin Pharmacol study. Neurobiol Aging 34: 91-99 (2013).
26: 74-79 (2016). [116] Pelvig DP, Pakkenberg H, Stark AK, Pakkenberg B. Neocortical
[96] DeWitt DA, Perry G, Cohen M, Doller C, Silver J. Astrocytes glial cell numbers in human brains. Neurobiol Aging 29: 1754-
regulate microglial phagocytosis of senile plaque cores of Alz- 1762 (2008).
heimer's disease. Exp Neurol 149: 329-340 (1998). [117] Diniz DG, Foro CA, Rego CM, Gloria DA, de Oliveira FR, Paes
[97] Abramov AY, Canevari L, Duchen MR. Changes in intracellular JM, et al. Environmental impoverishment and aging alter object
calcium and glutathione in astrocytes as the primary mechanism of recognition, spatial learning, and dentate gyrus astrocytes. Eur J
amyloid neurotoxicity. J Neurosci 23: 5088-5095 (2003). Neurosci 32: 509-519 (2010).
[98] Abramov, AY. Canevari, L. Duchen, MR. -Amyloid peptides [118] Cerbai F, Lana D, Nosi D, Petkova-Kirova P, Zecchi S, Brothers
induce mitochondrial dysfunction and oxidative stress in astrocytes HM, et al. The neuron-astrocyte-microglia triad in normal brain
and death of neurons through activation of NADPH oxidase. J Neu- ageing and in a model of neuroinflammation in the rat hippocam-
rosci 24: 565-575 (2004). pus. PLoS One 7: e45250 (2012).
[99] Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ. Synchro- [119] Rodriguez JJ, Yeh CY, Terzieva S, Olabarria M, Kulijewicz-
nous hyperactivity and intercellular calcium waves in astrocytes in Nawrot M, Verkhratsky A. Complex and region-specific changes in
Alzheimer mice. Science 323: 1211-1215 (2009). astroglial markers in the aging brain. Neurobiol Aging 35: 15-23
[100] Matos, M. Augusto E, Oliveira CR, Agostinho P. Amyloid-beta (2014).
peptide decreases glutamate uptake in cultured astrocytes: in- [120] Grosche A, Grosche J, Tackenberg M, Scheller D, Gerstner G,
volvement of oxidative stress and mitogen-activated protein kinase Gumprecht A, et al. Versatile and simple approach to determine as-
cascades. Neuroscience 156: 898-910 (2008). trocyte territories in mouse neocortex and hippocampus. PLoS One
[101] Hartlage-Rubsamen M, Zeitschel U, Apelt J, Gartner U, Franke H, 8: e69143 (2013).
Stahl T, et al. Astrocytic expression of the Alzheimer's disease - [121] Sampedro-Piquero P, De Bartolo P, Petrosini L, Zancada-
secretase (BACE1) is stimulus-dependent. Glia 41: 169-179 Menendez C, Arias JL, Begega A. Astrocytic plasticity as a possi-
(2003). ble mediator of the cognitive improvements after environmental en-
[102] Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter richment in aged rats. Neurobiol Learn Mem 114: 16-25 (2014).
J, et al. Focal glial activation coincides with increased BACE1 ac-
Glia in Alzheimers Disease and Ageing Current Alzheimer Research, 2016, Vol. 13, No. 4 357

[122] Lalo U, Palygin O, North RA, Verkhratsky A, Pankratov, Y. Age- [144] Psachoulia K, Jamen F, Young KM, Richardson WD. Cell cycle
dependent remodelling of ionotropic signalling in cortical astroglia. dynamics of NG2 cells in the postnatal and ageing brain. Neuron
Aging Cell 10: 392-402 (2011). Glia Biol 5: 57-67 (2009).
[123] Kress BT, Iliff JJ, Xia M, Wang M, Wei H, Zeppenfeld D, et al. [145] Simon C, Gotz M, Dimou L. Progenitors in the adult cerebral cor-
Impairment of paravascular clearance pathways in the aging brain. tex: cell cycle properties and regulation by physiological stimuli
Ann Neurol 76: 845-861 (2014). and injury. Glia 59: 869-81 (2011).
[124] Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M, [146] Bowley MP, Cabral H, Rosene DL, Peters A. Age changes in mye-
Soininen H. Astrocytes in the aging brain express characteristics of linated nerve fibers of the cingulate bundle and corpus callosum in
senescence-associated secretory phenotype. Eur J Neurosci 34: 3- the rhesus monkey. J Comp Neurol 518: 3046-3064 (2010).
11 (2011). [147] Bartzokis G. Alzheimer's disease as homeostatic responses to age-
[125] Matute C. Calcium dyshomeostasis in white matter pathology. Cell related myelin breakdown. Neurobiol Aging 32: 1341-71 (2009).
Calcium 47: 150-157 (2010). [148] Brant-Zawadzki M, Fein G, Van Dyke C, Kiernan R, Davenport
[126] Bartzokis G. Alzheimer's disease as homeostatic responses to age- L, de Groot J. MR imaging of the aging brain: patchy white-matter
related myelin breakdown. Neurobiol Aging 32: 1341-71 (2009). lesions and dementia. AJNR Am J Neuroradiol 6: 675-682 (1985).
[127] Shields SA, Gilson JM, Blakemore WF, Franklin RJ. Remyelina- [149] McLachlan DR, Wong L, Bergeron C, Baimbridge KG.
tion occurs as extensively but more slowly in old rats compared to Calmodulin and calbindin D28K in Alzheimer disease. Alzheimer
young rats following gliotoxin-induced CNS demyelination. Glia Dis Assoc Disord 1: 171-179 (1987).
28: 77-83 (1999). [150] Larsson E, Passant U, Sundgren PC, Englund E, Brun A, Lindgren
[128] Franklin RJ. Why does remyelination fail in multiple sclerosis? A, et al. Magnetic resonance imaging and histopathology in de-
Nature reviews. Neuroscience 3(9): 705-714 (2002). mentia, clinically of frontotemporal type. Dement Geriatr Cogn
[129] Sim FJ, Zhao C, Penderis J, Franklin RJ. The age-related decrease Disord 11: 123-134 (2000).
in CNS remyelination efficiency is attributable to an impairment of [151] Yoshida M. Amyotrophic lateral sclerosis with dementia: the clini-
both oligodendrocyte progenitor recruitment and differentiation. J copathological spectrum. Neuropathology 24: 87-102 (2004).
Neurosci 22: 2451-2459 (2002). [152] Steffens DC, Potter GG, McQuoid DR, MacFall JR, Payne ME,
[130] Shen S, Sandoval J, Swiss VA, Li J, Dupree J, Franklin RJ, Casac- Burke JR, et al. Longitudinal magnetic resonance imaging vascular
cia-Bonnefil P. Age-dependent epigenetic control of differentiation changes, apolipoprotein E genotype, and development of dementia
inhibitors is critical for remyelination efficiency. Nat Neurosci 11: in the neurocognitive outcomes of depression in the elderly study.
1024-1034 (2008) . Am J Geriatr Psychiatry 15: 839-849 (2007).
[131] Salter MG, Fern R. NMDA receptors are expressed in developing [153] Staekenborg SS, Koedam EL, Henneman WJ, Stokman P, Barkhof
oligodendrocyte processes and mediate injury. Nature 438: 1167- F, Scheltens P, et al. Progression of mild cognitive impairment to
1171 (2005). dementia: contribution of cerebrovascular disease compared with
[132] Butt AM, Duncan A, Hornby MF, Kirvell SL, Hunter A, Levine medial temporal lobe atrophy. Stroke 40: 1269-1274 (2009).
JM, et al. Cells expressing the NG2 antigen contact nodes of Ran- [154] Bronge L. Magnetic resonance imaging in dementia. A study of
vier in adult CNS white matter. Glia 26: 84-91 (1999). brain white matter changes. Acta Radiol Suppl (428): 1-32 (2002).
[133] Hamilton N, Vayro S, Wigley R, Butt AM. Axons and astrocytes [155] Brown WR, Moody DM, Thore CR, Challa VR. Cerebrovascular
release ATP and glutamate to evoke calcium signals in NG2-glia. pathology in Alzheimer's disease and leukoaraiosis. Ann N Y Acad
Glia 58: 66-79 (2010). Sci 903: 39-45 (2000).
[134] Kukley M, Capetillo-Zarate E, Dietrich D. Vesicular glutamate [156] Mattson MP, Chan SL. Neuronal and glial calcium signaling in
release from axons in white matter. Nat Neurosci 10: 311-320 Alzheimer's disease. Cell Calcium 34: 385-397 (2003).
(2007). [157] Xu J, Chen S, Ahmed SH, Chen H, Ku G, Goldberg MP, Hsu CY.
[135] Wake H, Lee PR, Fields RD. Control of local protein synthesis and Amyloid-beta peptides are cytotoxic to oligodendrocytes. J Neuro-
initial events in myelination by action potentials. Science 333: sci 21: RC118 (2001).
1647-1651 (2011). [158] Pak K, Chan SL, Mattson MP. (Presenilin-1 mutation sensitizes
[136] Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood oligodendrocytes to glutamate and amyloid toxicities, and exacer-
LS, et al. Neuronal activity promotes oligodendrogenesis and adap- bates white matter damage and memory impairment in mice. Neu-
tive myelination in the mammalian brain. Science 344: 1252304 romol Med 3: 53-64 (2003).
(2014). [159] Jantaratnotai N, Ryu JK, Kim SU, McLarnon JG. Amyloid beta
[137] Gallo V, Zhou JM, McBain CJ, Wright P, Knutson PL, Armstrong peptide-induced corpus callosum damage and glial activation in
RC. Oligodendrocyte progenitor cell proliferation and lineage pro- vivo. Neuroreport 14: 1429-1433 (2003).
gression are regulated by glutamate receptor-mediated K+ channel [160] Desai MK, Sudol KL, Janelsins MC, Mastrangelo MA, Frazer
block. J Neurosci 16: 2659-2670 (1996). ME, Bowers WJ. Triple-transgenic Alzheimer's disease mice ex-
[138] Gudz TI, Komuro H, Macklin WB. Glutamate stimulates oligoden- hibit region-specific abnormalities in brain myelination patterns
drocyte progenitor migration mediated via an alphav in- prior to appearance of amyloid and tau pathology. Glia 57: 54-
tegrin/myelin proteolipid protein complex. J Neurosci 26: 2458- 65(2009).
2466 (2006). [161] Burns JM, Church JA, Johnson DK, Xiong C, Marcus D, Fotenos
[139] Lundgaard I, Luzhynskaya A, Stockley JH, Wang Z, Evans KA, AF, et al. White matter lesions are prevalent but differentially re-
Swire M, et al. Neuregulin and BDNF induce a switch to NMDA lated with cognition in aging and early Alzheimer disease. Arch
receptor-dependent myelination by oligodendrocytes. PLoS Biol Neurol 62: 1870-1876 (2005).
11: e1001743 (2014). [162] Nielsen HM, Ek D, Avdic U, Orbjrn C, Hansson O, Netherlands
[140] Pickel VM, Garzn M, Mengual E. Electron microscopic immuno- BB, et al. NG2 cells, a new trail for Alzheimer's disease mecha-
labeling of transporters and receptors identifies transmitter-specific nisms? Acta Neuropathol Commun 1: 7 (2013).
functional sites envisioned in Cajals neuron. Prog Brain Res 136: [163] McGeer EG, McGeer PL. Brain inflammation in Alzheimer disease
145-55 (2002). and the therapeutic implications. Curr Pharm Des 5: 821-836
[141] Stys PK. The axo-myelinic synapse. Trends Neurosci 34: 393-400 (1999).
(2011). [164] Heneka MT, O'Banion MK. Inflammatory processes in Alzheimer's
[142] Etxeberria A, Mangin JM, Aguirre A, Gallo V. Adult-born SVZ disease J Neuroimmunol 184: 69-91 (2007).
progenitors receive transient synapses during remyelination in cor- [165] Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K,
pus callosum. Nat Neurosci 13: 287-289 (2010). et al. Microglial response to amyloid plaques in APPsw transgenic
[143] Peters, A. Verderosa A, Sethares C. The neuroglial population in mice. Am J Pathol 152: 307-317 (1998).
the primary visual cortex of the aging rhesus monkey. Glia 56: [166] Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, et
1151-1161 (2008). al. Dynamics of the microglial/amyloid interaction indicate a role
in plaque maintenance. J Neurosci 28: 4283-4292 (2008).
358 Current Alzheimer Research, 2016, Vol. 13, No. 4 Rodrguez et al.

[167] Barger SW, Harmon AD. Microglial activation by Alzheimer amy- [171] Lotz M, Ebert S, Esselmann H, Iliev AI, Prinz M, Wiazewicz N, et
loid precursor protein and modulation by apolipoprotein E. Nature al. Amyloid b peptide 1-40 enhances the action of Toll-like recep-
388: 878-881 (1997). tor-2 and -4 agonists but antagonizes Toll-like receptor-9-induced
[168] Schubert P, Morino T, Miyazaki H, Ogata T, Nakamura Y, Mar- inflammation in primary mouse microglial cell cultures. J Neuro-
chini C, et al. Cascading glia reactions: a common pathomecha- chem 94: 289-298 (2005).
nism and its differentiated control by cyclic nucleotide signaling. [172] Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Aru-
Ann NY Acad Sci 903: 24-33 (2000). mugam TV. Toll-like receptors in neurodegeneration. Brain Res
[169] Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, Rev 59: 278-292 (2009).
de Calignon A, Rozkalne A, et al. Rapid appearance and local tox- [173] Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, et al.
icity of amyloid-beta plaques in a mouse model of Alzheimer's dis- Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's
ease. Nature 451: 720-724 (2008). disease. Cell Physiol Biochem 20: 947-956 (2007).
[170] Sanz JM, Chiozzi P, Ferrari D, Colaianna M, Idzko M, Falzoni S, [174] Ohm TG. The dentate gyrus in Alzheimers disease. Prog Brain
et al. Activation of microglia by amyloid b requires P2X7 receptor Res 163: 723-40 (2007).
expression. J Immunol 182: 4378-4385 (2009).

Received: December 13, 2015 Revised: February 03, 2016 Accepted: February 04, 2016