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Complex and differential glial responses in

Alzheimers disease and ageing

Article in Current Alzheimer research April 2016

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

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344 Current Alzheimer Research, 2016, Vol. 13, No. 4
The defence system of the CNS (separated from the rest
of the body by the blood-brain barrier) is formed and con-
trolled by glia, which are highly sensitive and responsive to
environmental stress and pathological insults. CNS lesions,
regardless of their nature, trigger evolutionarily conserved
cascades of glial "damage" responses, generally known as
reactive gliosis. Glial reactivity is characterized not only by
morphological remodelling [36], but also by functional re-
modelling [27], depending on the pathological process. As-
trocytes generally undergo reactive astrogliosis [37, 38],
critical for both sealing the damaged area through scar for-
mation (anisomorphic astrogliosis), and for neuroprotection
and post-insult remodelling of neural circuits (isomorphic
astrogliosis) [27, 36]. Oligodendrocytes, on the other hand,
undergo Wallerian degeneration [39, 40], which is closely
associated with a slow generation of new oligodendrocytes
through proliferation and differentiation of NG2-glia cells, to
counteract the loss of oligodendrocytes and myelin [9, 10,
41, 42]. Finally, microglial cells react to CNS damage by a
multi-stage and complex process of microglial activation and
active recruitment [30, 31, 43-47], which underlies immune
and phagocytic responses of the nervous tissue.
The complementary orchestration of glial defensive cas-
cades defines the progression and outcome of virtually all
neurological diseases, at both acute and chronic stages [30,
31, 48-51]. Astrocytes are specifically important for the pro-
gression of acute brain insults, such as trauma and stroke
[52, 53], as well as for pathophysiology of chronic neuro-
logical disorders [54], such as epilepsy, depression and
schizophrenia, where astrocytes display degenerative and
pathological signs. Astrocytes (both pre-existing and newly
generated through gliogenesis) are actively involved in re-
generation aimed at the restoration of the affected neural
networks as well as the neural-glial-vascular units [49, 55-
58]. Oligodendrocytes are central to diseases of white matter,
which accounts for > 50% of the overall brain volume in
humans, and is critical for rapid integrative brain function
through the axonal support and myelination [56-58]. Damage
to oligodendroglia are fundamental for demyelinating disor-
ders, including multiple sclerosis [30, 31, 62-65]. In this re-
spect, NG2-glia are key to white matter pathology, since
they are responsible for the regeneration of oligodendrocytes
and remyelination, which is essential to recovery and repair
[9, 10]. Microglial cells, as the immune and phagocytic ele-
ments of the CNS are, therefore, involved in every type of
neuropathology; contributing to associated neuroinflamma-
tory responses [30, 31, 43, 47, 66].
Neurodegenerative diseases invariably commence from
altered synaptic and non-synaptic contacts between neural
cells. This early stage of neurodegeneration is extremely
important, because when appropriately tackled, neurodegen-
eration can be arrested or even reversed, thus preventing
cognitive decline and even restoring cognitive function. The
disruption of glial maintenance of synaptic connectivity is a
key element in the early stages of neurodegenerative proc-
esses. It is poorly recognised that, in addition to classic glial
reactivity, neurodegeneration is associated with gliodegen-
eration, with a corresponding loss of glial function. Astrode-
generation often precedes astrogliosis, the latter being re-
garded as a general reaction at the later stages of the disease.
In amyotrophic lateral sclerosis (ALS), for example, as-
Rodrguez et al.
trodegeneration and astroglial atrophy are central pathologi-
cal factors that preceded overt neuronal death and the ap-
pearance of clinical symptoms [30-32, 47, 64]. At the later
stages of the ALS, reactive astrogliosis becomes evident,
although the atrophic astrocytes are still present around le-
sion sites [50, 67, 68]. Importantly, the silencing of ALS-
related mutant SOD1 gene in astrocytes delayed the appear-
ance of clinical symptoms [30, 31, 69].
Astroglial loss of function represents the primary patho-
genic event in Wernicke encephalopathy, a substrate for
Korsakoff syndrome [70, 71]. The loss of astroglial function
is manifested by compromised glutamate homeostasis fol-
lowing down-regulation of astroglial glutamate transporters
EAAT1 and EAAT2. Failure in glutamate homeostasis insti-
gates neuronal excitotoxicity and severe brain lesions charac-
teristic for the disease [72, 73]. Similarly in Huntingtons
and Parkinsons diseases, loss of astroglial glutamate uptake,
an increase in astroglial glutamate, release contribute to neu-
rodegenerative progression [74-78].
Astrocytes are central elements of Alexanders disease, a
rare disorder that arises from mutations in glial fibrillary
acidic protein (GFAP), the major intermediate filament pro-
tein of astrocytes [79]. Although GFAP is expressed at lower
levels in a number of cell types throughout the body, evi-
dence points to initial dysfunction of astrocytes as the key
initiating event that then leads to a cascade of effects, ulti-
mately affecting every other cell type in the CNS [80].
2. ASTROCYTES IN DEMENTIA AND ALZ-
HEIMERS DISEASE
2.1. Dementia
Astrocytes display pathological changes of both atrophic
and reactive nature in various forms of non-AD dementia. In
frontotemporal dementia, astrocytes undergo early apoptotic
death and dystrophy [81, 82], which correlates with the se-
verity of dementia. Post-mortem tissues are heavily popu-
lated with reactive astrocytes, with up to 5 times increase in
astrocyte density being detected in some studies [79]. An
astrogliotic response was also found in thalamic dementia,
where pathological remodelling was specifically observed in
perivascular and perineuronal astroglial processes. Both as-
trogliosis and astroglial apoptosis and astrodegeneration
were detected in immunodeficiency virus-1 (HIV-1) associ-
ated dementia (HAD) [30, 31, 83-85], being observed in sub-
jects with rapidly progressing cognitive deficits [86].
2.2. Alzheimers Disease
AD appears in both genetic (family Alzheimer's disease
or FAD) and sporadic (SAD) forms [87]. AD is characterised
by progressive neurodegeneration, the histopathological
hallmarks of the disease being (i) focal extracellular deposits
of fibrillar -amyloid (also called neuritic or senile plaques)
in brain parenchyma and in the wall of blood vessels, and (ii)
intraneuronal accumulation of neurofibrillary tangles origi-
nating from the abnormal hyperphosphorylation of tau fila-
ments [30-32, 88-92]. The initial neurodegenerative events
in AD appear in the transentorhinal cortex, spreading to the
entorhinal cortex (EC) and hippocampus; at the later stages
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,
the grey matter undergoes severe damage manifested by a
profound loss of neurones and synaptic contacts.
The role of astrocytes in the pathogenesis and progres-
sion of AD is not yet clear. It is generally agreed that at the
late stages of the disease (as shown by post-mortem tissues
analysis) there is a prominent reactive astrogliosis and inclu-
sion of astrocytes and microglial cells into senile plaques
[51, 90, 91]. This pathology was initially identified by Alois
Alzheimer , who described glial cells as an integral part of
the neuritic plaque [92-95] (Fig. 1).
Identification of molecules and/or components of AD
pathology that trigger astrogliosis remain to be determined,
although several lines of evidence indicate that -amyloid
peptide (A) by itself seems to be an activating signal. For
example, exposure of primary glial cell cultures to aggregate
-amyloid or to amyloid plaques isolated from human AD
brains induces reactive astrogliosis [96]. Simultaneously, A
may trigger astrocytic calcium (Ca2+) signals (represented by
both [Ca2+]i transients and [Ca2+]i oscillations) in astroglial-
neuronal co-cultures [97]. These Ca2+ oscillations are some-
how involved in A-induced neurotoxicity, probably through
the release of reactive oxygen species from A-stimulated
astrocytes [32, 98]. Abnormal Ca2+ signalling was also ob-
served in vivo, in transgenic AD mouse models, evinced as
an anomalous spontaneous Ca2+ wave propagation in astro-
cytes located in the vicinity of neuritic plaques [99]. A was
also reported to decrease expression and activity of GLAST-
and GLT-1 mediated glutamate uptake in cultured astrocytes
[100].
The question of whether astrocytes participate in produc-
tion/sequestration of A in AD remains debatable. Astro-
cytes from mice expressing double mutated
Tg(APPSWE)2576Kha (K670N-M671L APP) were reported
to express -secretase, thus being able to produce A [30,
31, 101, 102]. On the other hand, there are some indications
that astrocytes may accumulate (questionably by phagocyto-
sis) and degrade A, thereby reducing A load [90]. For
example, accumulation of A was observed in astrocytes
from entorhinal cortex of AD patients [103]. In support of
this, astrocytes isolated from healthy brains migrated to-
wards plaques and accumulated A when plated onto brain
slices isolated from mutant APP transgenic mice. In contrast,
astrocytes isolated from the APP mice were unable to clear
A loads [104]. Similarly, very little (if any) A accumula-
tion by reactive astrocytes surrounding plaques was observed
in 3xTg-AD mice [30-32, 91, 105].
These studies suggest the interactions of astrocytes with
A are not straightforward and may depend on their reactive
state. Studies in the 3xTg-AD mouse model demonstrate
astrocytes undergo complex pathological changes, depending
on the brain area and stage of the disease, whilst the total
number of astrocytes remained stable, even up to 24 month
in any of the mnesic areas relevant to AD [105, 106]. At the
early stages of the disease (i.e. pre-plaque), astrocytes in
hippocampus and entorhinal cortex (EC) demonstrate signs
of atrophy and degeneration [29, 91, 94, 95, 105, 107, 108]
(Fig. 2). These changes are marked by reduced expression of
GFAP and decreased number and branching of cell proc-
esses, and are field specific in the hippocampus (DG & CA1)
and layer specific in the EC (layers II & VI) [29, 91, 94, 95
105, 107] (Fig 2). Astroglial atrophy the 3xTg-AD mouse
followed a specific course through the brain regions, compa-
rable to the neuropathology of human AD, commencing in
the EC (1 month of age), subsequently appearing in the pre-
frontal cortex (PFC, 3 months of age), and finally in the hip-
pocampus (9 - 12 months of age) [105, 107, 108] (Fig. 2). At
the later stages of the disease, plaque formation and accumu-
lation triggers an astrogliotic reaction exclusively in the hip-
pocampus and not in the EC or PFC, characterised by

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
plaques and -amyloid loaded blood vessels [30-32, 91, 105,
107, 108] (Figs. 3, 4). In addition, astrocytic glutamate me-
tabolism was affected in both hippocampus and PFC, but not
in the EC, as shown by a decrease in GS expression and
number of anti-GS-immunolabeled astrocytes [106, 109,
110] (Fig. 5).
These differential changes in astrocytes appear to be di-
rectly associated with the specific vulnerability of different
brain regions to AD type pathology [26]. Furthermore, early
atrophy of astroglial cells would have important functional
consequences affecting synaptic coverage and functional
performance of neuronal-glial-vascular units. Astroglial me-
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
glymphatic system and therefore in protein waste clearance
[123]. There is emerging evidence for astrocytes acquiring a
senescence-associated secretory phenotype, characterised by
an increased expression of cytokines and accumulation of
proteotoxic aggregates [124].
3. OLIGODENDROGLIA, MYELIN AND NG2-GLIA
IN DEMENTIA AND ALZHEIMERS DISEASE
Oligodendrocytes are the major cell type of CNS white
matter, which in humans represents around 50% of brain
volume, but are also present in the grey matter and in par-
ticular throughout the cerebral cortex [30, 31, 59, 61]. Pri-
mary and/or secondary oligodendrocyte death and myelin
damage occurs in most, if not all, CNS diseases, including
stroke, perinatal ischemia, multiple sclerosis, psychiatric
disorders, traumatic injury and AD [125].
Myelination increases during postnatal development,
peaks at around 45 years and subsequently decreases to in-
fancy levels as age approaches 100 years [126]. The life-long
generation of new oligodendrocytes and myelin is a function
of oligodendrocyte precursors (OPs), also known as NG2-
glia or polydendrocytes. However, myelin loss is evident
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
and release of proapoptotic factors that activate caspases
[125, 131]. Glutamate and ATP excitotoxicity constitute an
important disease mechanism, since these are among the
most abundant molecules in brain tissue and acute transient
alterations in their homeostasis as well as chronic pathologi-
cal states can over-activate their receptors and damage oli-
godendroglia and myelin [60, 125]. However, the extent to
which excitotoxicity contributes directly to demyelination in
aging and dementia is not known.
In parallel, there is evidence that NG2-glia need gluta-
mate signalling for myelination through the synapses they
form with the neighbour neurons and axons [132-136]. NG2-
glia proliferate and migrate via AMPA receptor activation,
whilst the signal for myelination arrives via NMDA recep-
tors [135, 137-139]. The AMPA and NMDA receptors are
expressed in mature oligodendrocyte somata and myelin,
respectively [132, 140], and this has led to the hypothesis
that communication between axons and myelin represents a
new type of axon-myelin synapse [141]. After demyelina-
tion, the formation of neuron-NG2-glia synapses suggests
that synaptic glutamate signalling is important for the early
stages of remyelination [142]. Thus, myelina-
tion/remyelination is dependent on axonal activity and glu-
tamatergic signalling even in adulthood [42].
3.1. Ageing and Dementia
The effects of age on oligodendrocytes and myelin have
been recently examined experimentally in the primary visual
cortices of rhesus monkeys that had been also behaviourally
tested [143]. Alterations in myelin sheaths increase with age
being an age-related increase in the frequency of profiles of
nerve fibres sectioned through paranodes, indicating that
shorter lengths of myelin are being produced by remyelina-
tion. In addition, alterations in myelin correlate with the
number of oligodendrocytes, suggesting that with age newly
generated oligodendrocytes are required to remyelinate nerve
fibres. For this of course is needed an active presence and
proliferation of NG2-glia, which in an equivalent manner
also decreases the rate of self renewal with age [9, 125, 144,
145].
These data suggest that structural integrity of myelin
sheaths deteriorates during ageing and leads to impaired effi-
ciency in information flow along neural networks and thus to
cognitive decline. This is supported by MRI studies of the
human corpus callosum indicating breakdown of white mat-
ter structural integrity in ageing [30, 31, 146] and a 20%
decrease in the number of myelinated nerve fibres in the cor-
pus callosum and fibre tracts associated with frontal lobe
areas in ageing monkeys [125, 147]. Moreover, these obser-
vations imply that inter-hemispheric connectivity of the fron-
tal lobes is most severely affected and, consequently, mal-
function of cognition-related areas [146].
Early MRI studies of patients with non-Alzheimer de-
mentia have also shown diffuse, patchy white matter lesions
in all cases examined [148]. The grade of severity of the
changes and the prevalence observed was higher than in
cognitively normal subjects. Interestingly, calcium binding
proteins calmodulin and calbindin have altered expression
and function in the white matter of non-Alzheimer dementia
Current Alzheimer Research, 2016, Vol. 13, No. 4 351
patients [30, 31, 149]. Thus, calmodulin has reduced efficacy
in activating 3',5' cyclic nucleotide phosphodiesterase
(CNPase), which is exclusively and constitutively expressed
in oligodendrocytes, whereas calbindin has reduced levels in
white matter [30, 31, 149].
Recent studies have provided more details about the na-
ture of the damage to white matter and the type of non-
Alzheimer dementia. Thus, patients with frontotemporal de-
mentia show ischemic-like primary incomplete infarction of
frontal white matter, which shows gliosis and demyelination
[30, 31, 150], and those with ALS-related dementia display
diffuse fibrous gliosis in frontotemporal white matter [151].
In turn, depressed patients with mild non-Alzheimer demen-
tia have changes in white matter MRI hyperintensity vol-
umes [152], a feature that also occurs in vascular dementia
[153]. Importantly, these changes in hyperintensity have
predictive value for the onset and progression of dementia
[152, 153].
3.2. Alzheimers Disease
It is well known that white matter is altered in AD. White
matter alteration in specific areas of the brain during the pro-
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
[154]. A high percentage of AD patients exhibit evidence of
white matter degeneration with severe loss of oligodendro-
cytes by apoptosis [125, 155]. Despite the fact that the
mechanisms underlying this damage are not well understood,
it is clear that they involve both, amyloidoisis and Ca2+ dy-
shomeostasis [125, 156].
-amyloid peptides can damage oligodendrocytes in vitro
[157] and increase their vulnerability to glutamate toxicity
[125, 158]. Injection of amyloid 1-42 into white matter
causes axon disruption and myelin damage, as well as oli-
godendrocyte loss and profound gliosis [125, 159]. In the
presenilin-1 mutant knock-in mice are more susceptible to
glutamate excitotoxicity and exhibit an abnormality in Ca2+
regulation, which is responsible for their demise [158].
Moreover, when exposed to the demyelinating agent cupri-
zone, this model exhibit enhanced white matter damage and
learning and memory deficits compared to wild-type mice
[125, 158]. Thus, specific presenilin-1 mutation in oligoden-
drocytes has detrimental effects leading to disease, and indi-
cate that white matter damage may well contribute to cogni-
tive dysfunction in AD.
In 3xTg-AD mice, significant region-specific alterations
in myelination patterns and in oligodendrocyte marker ex-
pression profiles were observed at time points preceding the
appearance of amyloid and tau pathology [30, 31, 160].
These findings indicate that myelin and oligodendrocyte
defects in AD occur before the onset of symptoms and may
be key players in the development of this disease. Indeed,
lesions are prevalent in early-stage AD, in periventricular
and deep white matter [30, 31,161]. Notably, the burden of
both types of lesions is associated with reduced global cogni-
tion, as assessed by evaluating visual memory, processing
speed and executive function.
352 Current Alzheimer Research, 2016, Vol. 13, No. 4
In addition, we have detected marked changes in NG2-
glia in 3xTg-AD mice, throughout the full extension of the
hippocampus, as shown by an evident atrophy at early stages
of the disease, before the presence of A plaques [63]. NG2-
glia in age-matched non-Tg mice have a characteristic multi-
processed morphology and often appear as duplets or trip-
lets, indicating recent division, which was significantly de-
creased in 3xTg-AD mice [42]. Note that NG2-glia divide
asymmetrically to form sister NG2-glia, one for self-
renewal and the other differentiates into an oligodendrocyte.
The decrease in sister NG2-glia in 3xTg-AD mice correlated
with retraction of their processes, implying a loss of NG2-
glial cell synaptic connectivity may be linked to reduced
regenerative capacity of NG2-glia and myelin loss. At later
stages, when the pathological burden is high, in the 24-
month 3xTg-AD brain and hippocampus, NG2-glia are hy-
pertrophic and intimately associated with A plaques, which
appear to be circumscribed by NG2-glia and infiltrated by
their processes. This is consistent with changes in NG2-glia
in human AD [162]. These studies indicate that atrophy of
NG2-glia is an early feature of AD, concomitant with myelin
loss and synaptic dysfunction, whereas at later stages NG2-
glia contribute with astrocytes to the inhibitory environment
of the glial scar in response to patent neuropathology.
3.3. Relevance of Oligodendrocyte and Myelin to Demen-
tia and AD
White and grey matter oligodendrocytes and their precur-
sors NG2-glia are key cells for information flow in myeli-
nated axons. Cognitive deficits associated with AD and non-
AD dementia are paralleled by alterations in myelin patterns.
Furthermore, the myelin sheath is not just an inert insulating
structure and is essential for the long-term integrity of mye-
linated axons [23, 27, 42, 132, 133]. Hence, rescuing the loss
of myelin is an important target for protecting against irre-
versible neurodegenerative changes. Moreover, recent stud-
ies provide evidence that neuron-NG2-glial cell interactions
are important for synaptic function and integrity in dementia-
relevant brain regions [23, 27, 42, 132, 133]. For example,
ablation of NG2-glia in the prefrontal cortex of the adult
brain causes deficits in excitatory glutamatergic neurotrans-
mission and induces depressive-like behaviour in mice [23,
27, 42, 132, 133]. Consequently, novel, effective oligo- and
myelin-protective strategies ought to be developed to treat
more efficiently these disorders. A feasible approach is to
explore the therapeutic potential of specific drugs aiming at
restoring Ca2+ homeostasis.
4. MICROGLIA IN DEMENTIA AND ALZHEIMERS
DISEASE
Neuroinflammation contributes to physiological and
pathophysiological aging, including AD. Activation of mi-
croglia occurs simultaneously with the formation of neuritic
plaques [51, 163]. Microglial cells together with astrocytes
are closely associated with senile plaques, and they fuel the
neuroinflammatory process by secreting multiple pro-
inflammatory factors [164]. Furthermore, activated micro-
glial cells phagocytose -amyloid, thus reducing its load
[165, 166].
Rodrguez et al.
Microglial activation in AD brains has multiple origins
and nature, including amyloid peptides, APP and different
molecules released by damaged neurones and activated as-
trocytes [167, 168]; whether it is soluble A or consolidated
plaques, which act as the ultimate activating signal remains
unclear [48]. Recent studies using in vivo multiphoton mi-
croscopy on 5 - 6 month old B6C3-YFP transgenic mice
(harbouring APPswe and PS1d9x-YFP genes) demonstrated
that microglia are activated and recruited to A plaques only
after they have been formed [169]. In contrast, in APP V717I
transgenic mice, microglial activation was observed at 3
months of age, whilst plaques only appear at ~ 10 - 12
months of age [102].
Microglial activation by A and senile plaques may in-
volve multiple receptors and signalling cascades. For exam-
ple, AD-associated activation of microglia requires P2X 7
purinoceptors and Ca2+ signalling [30-31, 170]. The role of
P2X7 receptors was specifically highlighted by recent ex-
periments in which intra-hippocampal injection of A1-42
failed to induce microglial activation in animals deficient in
P2X7 receptors [30-31, 170]. Microglial activation in AD
also involves Toll-like receptors of TLR4 and TLR2 type
[171, 172]. These receptors are up-regulated in AD animal
models and in post-mortem AD brains [172]. Incidentally, a
spontaneous loss-of-function mutation in the TLR4 gene
markedly decreased microglial activation induced by A [31,
32, 173, 174].
The longitudinal AD-induced reactions of microglia are
complex. In 3xTg-AD mice, we have found a substantial
increase in the density of resting (tomato-lectin positive)
microglia at both early (i.e. pre-plaque) and late stages of the
disease [44]. At 9 month of age (when the senile plaques are
virtually absent), the density of resting microglia in the hip-
pocampus of 3xTg-AD was ~105% larger than in control
mice. This increased density of resting microglia remains at
older ages (at 12 months it was 54% higher and at 18 month
131% higher compared to the controls). The appearance of
plaques triggered microglial activation [44-46, 107, 108].
(Fig. 4B); we observed a significant increase in the density
of activated microglia in CA1 hippocampal area of 3xTg-AD
mice at 12 and 18 months, which correlated with the age of
the appearance and development of A plaques [44-46] (Fig.
8). The early increase in the density of resting microglia may
represent the generalized response of the brain defence sys-
tem to the developing AD pathology.
Increased densities of resting and activated microglia in
the dentate gyrus follow senile plaque formation in the CA1
subfield of the hippocampus, which is consistent with the
later involvement of DG in the human pathology [42, 167].
Compared to non-Tg controls, 3xTg-AD mice displayed a
significant increase in resting (by 75%) and activated (by
67%) microglia in the molecular layer of the DG at 18
months of age [44-46] (Fig. 8F-G). These results indicate a
complex microglial remodelling during AD progression and
a specific order of progress within the hippocampal circuitry,
reacting first in CA1 followed by the DG.
Psychostimulation, such as running (RUN) and enriched
environment (ENR), prevented this global microglial hippo-
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
5. FINAL REMARKS
All glial cells types contribute to the progression of Alz-
heimer's disease and ageing. The early AD astrocytic atrophy
reduces synaptic coverage and support, leading thus to
weakening of synaptic connectivity associated with early
cognitive deficits. Formation of -amyloid plaques induces
reactive astrogliosis exclusively in the hippocampus but not
in cortical areas; reactive astrocytes are specifically associ-
ated with -amyloid plaques. Reactive astrocytes contribute
not only to neurotoxicity but also to neuroinflammation,
through the release of pro-inflammatory factors and neuro-
toxic agents. Atrophy and degeneration of oligodendrocytes
results in white matter shrinkage, contributing to cognitive
decline and neurodegeneration. Altered regenerative capacity
of NG2-glia (OPs) will contribute to myelin loss in ageing
and this may be accelerated in AD. Finally, early recruitment
of ramified microglia and microglia activation at later stages
initiates and sustains the neuroinflammatory process that
results in cell death and brain atrophy.
DISCLOSURE
"Part of this article has been reproduced from author pre-
vious publication entitled "Neuroglia in Alzheimer's Dis-
ease" published in Frontiers in Neuroscience, in Astrocytes:
Wiring the brain. Eds. Scemes and Spray. Taylor and Fran-
cis, CRC Press. Pages 311-338."
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
We thank Drs. Chia-Yu Yeh, Magdalena Kulijewicz-
Nawrot, Markel Olabarria and Harun N. Noristani, for their
help and assistance in the figures. Authors research was sup-
ported by Alzheimers Research Trust (UK) Programme
Grant (ART/PG2004A/1) to AV and JJR; by National Insti-
tute of Health (NIH) grant to AV; by the Grant Agency of
the Czech Republic (GACR 309/09/1696) to JJR and
(GACR 305/08/1381 and GACR 305/08/1384) to AV as well
as by the Spanish Government,Plan Nacional de I+D+I
2008-2011, and ISCIII SubdireccinGeneral de Evaluacin y
Fomento de la investigacin co-financed by FEDER
(PI10/02738) to JJR and AV, and the Government of the
Basque Country grants (AE-2010-1-28; AEGV10/16,
GV2011111020) to JJR; and BBSRC grant to AB
(BB/M029379/1).
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Accepted: February 04, 2016