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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

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Arthur M Butt Vladimir Parpura


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Current Alzheimer Research, 2016, 13, 343-358 343

Complex and Differential Glial Responses in Alzheimers Disease and


Ageing

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


Alexei Verkhratsky1,2,6

1
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)
photograph
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-
cytes,

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;
E-mail: j.rodriguez-arellano@ikerbasque.org

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-
HEIMERS DISEASE
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-
[100].
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
[105].
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].
145].
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.

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[18] Magistretti PJ. Neuron-glia metabolic coupling and plasticity. J
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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-
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Received: December 13, 2015 Revised: February 03, 2016 Accepted: February 04, 2016