Astroglia in dementia and Alzheimer's disease

Abstract

Astrocytes, the most numerous cells in the brain, weave the canvas of the grey matter and act as the main element of the homoeostatic system of the brain. They shape the microarchitecture of the brain, form neuronal-glial-vascular units, regulate the blood-brain barrier, control microenvironment of the central nervous system and defend nervous system against multitude of insults. Here, we overview the pathological potential of astroglia in various forms of dementias, and hypothesise that both atrophy of astroglia and reactive hypertrophic astrogliosis may develop in parallel during neurodegenerative processes resulting in dementia. We also show that in the transgenic model of Alzheimer's disease, reactive hypertrophic astrocytes surround the neuritic plaques, whereas throughout the brain parenchyma astroglial cells undergo atrophy. Astroglial atrophy may account for early changes in synaptic plasticity and cognitive impairments, which develop before gross neurodegenerative alterations.

Full text

Review
Astroglia in dementia and Alzheimer’s disease
JJ Rodrı
´
guez*
,1,2
, M Olabarria
1
, A Chvatal
2
and A Verkhratsky*
,1,2
Astrocytes, the most numerous cells in the brain, weave the canvas of the grey matter and act as the main element of the
homoeostatic system of the brain. They shape the microarchitecture of the brain, form neuronal-glial-vascular units, regulate the
blood–brain barrier, control microenvirionment of the central nervous system and defend nervous system against multitude of
insults. Here, we overview the pathological potential of astroglia in various forms of dementias, and hypothesise that both
atrophy of astroglia and reactive hypertrophic astrogliosis may develop in parallel during neurodegenerative processes
resulting in dementia. We also show that in the transgenic model of Alzheimer’s disease, reactive hypertrophic astrocytes
surround the neuritic plaques, whereas throughout the brain parenchyma astroglial cells undergo atrophy. Astroglial atrophy
may account for early changes in synaptic plasticity and cognitive impairments, which develop before gross neurodegenerative
alterations.
Cell Death and Differentiation (2009) 16, 378–385; doi:10.1038/cdd.2008.172; published online 5 December 2008
Astrocytes, for the first time visualised by Otto Deiters
1
and
Christianised by Michael von Lenhossek
2
(for historical
overview, see also references
3,4
), are the main type of glia
in the central nervous system (CNS). The astrocytes, which
dwell in both grey and white matter, are the main element of
brain homoeostatic system, being responsible for all aspects
of metabolic support, nutrition, control of ion and neurotrans-
mitter environment, regulation of brain-blood barrier and
defence of the CNS.
5,6
In addition, astroglial cells are
endowed with numerous signalling cascades, which include
a wide array of plasmalemmal neurotransmitter receptors and
intracellular second messenger pathways.
7–10
These path-
ways in combination with trans-cellular communication routes
represented by gap junctions
11,12
and regulated gliotransmit-
ter release
13
support information processing within glial
networks, the mechanisms and functional relevance of which
remains essentially enigmatic.
The main type of astroglia in the grey matter, the
protoplasmic astrocytes, are characterised by complex
morphology with elaborated processes, which cover neuronal
membranes, residing within the astrocytic territories; the latter
being defined by the arborisation of a single astrocyte.
Importantly, a single-astroglial microanatomical domain is
essentially free from the processes of other astrocytes, giving
the grey matter in the brain and in the spinal cord a regular
parcellating structure.
14
A single astrocyte in the rodent brain
has a volume B66 000 mm
3
, and the membrane of this
astrocyte covers around 140 000 synapses lying within the
astroglial domain;
15
human astrocytes are considerably larger
and more complex and their processes wrap up to 2 millions of
synapses.
16
Protoplasmic astrocytes send processes to
neighbouring blood vessels, where these processes form
endfeet plastering the capillary wall and participating in
formation of blood–brain barrier. As a result, astroglial cells
integrate neurones and blood vessels into relatively indepen-
dent neuronal-glial-vascular units. Astroglial endfeet are
capable of releasing vasoactive substances that control local
blood flow and coordinate the latter with neuronal activity.
17–19
Individual astroglial domains are further integrated into an
internally continuous superstructure, because the peripheral
processes of astroglial cells are coupled through gap
junctions, which form a specific pathway for intercellular
communications binding astroglia into a functional syncytium.
This coupling most likely has anatomical specificity, providing
for specific organisation of glial networks: for example, in
somato-sensory cortex astroglial coupling is restricted to the
Received 25.7.08; revised 23.10.08; accepted 24.10.08; Edited by N Bazan; published online 05.12.08
1
Faculty of Life Sciences, The University of Manchester, Manchester, UK and
2
Institute of Experimental Medicine, ASCR, Videnska 1083, 142 20 Prague 4, Czech
Republic
*Corresponding authors: JJ Rodrı
´
guez, Faculty of Life Sciences, The University of Manchester, 1.124 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
E-mail: Jose.Rodriguez-arellano@manchester.ac.uk; Tel: þ 44 161 275 7324; Fax: þ 44 161 275 3938
or A Verkhratsky, Faculty of Life Sciences, The University of Manchester, 1.124 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
E-mail: alex.verkhratsky@manchester.ac.uk; Tel: þ 44 161 275 5414; Fax: þ 44 161 275 3938
Keywords: astrocyte; Glia/Alzheimer’s disease; dementia
Abbreviations: 3xTg-AD, triple-transgenic mice model of AD; AD, Alzheimer’s disease; APP, Amyloid precursor protein; APP/ApoE-KO, Double-transgenic mice
overexpressing a human mutated form of APP (APP
V717F
) in combination with ApoE gene knockout; APP
751SL
, Single-transgenic mice expressing APP mutation APP
Ser
751
to Leu; APP
751SL
/PS1
M146L
, Double-transgenic mice expressing APP
751SL
and PS1
M146L
; APP
SWE
, Single-transgenic mice expressing the ‘Swedish’ APP double-
point mutations Lys
670
to Asn and Met
671
to Leu; APP
SWE
/PS1
dE9
, Double-transgenic mice expressing APPswe and PS1
dE9
; CNS, central nervous system; FAD,
Familial form of Alzheimer’s disease; GFAP, glial fibrillary acidic protein; HAD, HIV-1-associated dementia; nAChR, nicotinic cholinoreceptor; nbm, nucleus basalis
magnocellularis; PDAPP, Single-transgenic mice expressing the ‘Swedish’ and ‘Indiana’ APP mutations Asp
664
to Ala (PDAPP(D664A); PS1, Preseniline 1; PS1
dE9
,
Single-transgenic mice (line S-9) expressing human PS1 carrying the exon 9-deleted variant associated with FAD; PS1
M146L
, Single-transgenic mice expressing PS1
mutation Met
146
to Leu; Tau
P301L
, Single-transgenic mice expressing the Pro
301
to Leu tau mutation (P301L)
Cell Death and Differentiation (2009) 16, 378–385
&
2009 Macmillan Publishers Limited All rights reserved 1350-9047/09
$
32.00
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barrel superstructure.
20
Gap junctions provide for inter-
cellular diffusion of variety of substances, including ions,
second messengers and metabolites such as glucose and
ATP.
21–23
This intercellular route underlies long-distance
communications within glial networks; one of the examples
of such communication is represented by glial calcium
waves;
21,24,25
yet propagating waves of other molecules can
also be relevant for intercellular signalling and information
processing.
26
Functional integration between neuronal and glial networks
is accomplished mainly through chemical transmission,
although there are incidental appearances of neuronal–glial
gap junctions.
27,28
Synaptic transmission in neuronal–glial
circuitry occurs either at the level of tripartite synapse (when
perisynaptic astroglial processes are directly exposed to
neurotransmitter released from the neuronal terminals,
29,30
)
or in neuronal–glial synapses.
31,32
The mechanisms of glia to
neurones signalling are more complex; at least in part they
may involve the exocytotic release of gliotransmitters.
13
Astroglia in neurological diseases
Progression and outcome of neurological diseases are
determined by the balance between destruction, neuroprotec-
tion and regeneration. In this context, glial cells are invariably
involved in every kind of neuropathology, which, to a very
large extent, is shaped by glial performance.
6,33
Astrocytes, in
accordance with their homoeostatic function, are deeply
involved in neural diseases. Astroglia forms the first line of
brain defence by controlling the volume and composition of
extracellular space. Astrocytes buffer an excess of extra-
cellular K
þ
, thus maintaining neuronal excitability,
34
control
extracellular levels of glutamate,
35,36
thereby limiting the
intrinsic excitotoxicity of the latter, regulate fluid movements
and provide the main antioxidant system in the brain.
37
At the
very same time astroglial cells can contribute to neuronal
damage, when, for example, severe insults compromise
astrocyte metabolism, which leads to a depolarisation and
reversal of glutamate uptake system, the latter underlying the
release of additional glutamate, thus exacerbating the brain
damage.
6
Acute and chronic brain insults trigger a specific glial
reaction, generally known as reactive astrogliosis, repre-
sented by a complex morphofunctional remodelling of astro-
cytes.
38
Reactive astrogliosis is a defensive brain reaction
which is aimed at (i) isolation of the damaged area from the
rest of the CNS tissue, (ii) reconstruction of the blood–brain
barrier and (iii) facilitation of the remodelling of brain circuits
in areas surrounding the lesioned region.
39,40
As a result,
astrogliosis comes in different guises. Astrocytes surrounding
the lesion undergo a robust hypertrophy and proliferation,
which ultimately ends up in complete substitution of previously
existing tissue architecture with a permanent glial scar;
this process is called anisomorphic (i.e., changing the
morphology) astrogliosis. In astrocytes more distal to the
damage, the reactive changes are much milder and, although
astroglial cells modify their appearance and undergo multiple
biochemical and immunological changes, they do not distort
the normal architecture of CNS tissue, but rather permit
growth of neurites and synaptogenesis, thus facilitating the
remodelling of neuronal networks. This type of astrocyte
reaction is defined as isomorphic (i.e., preserving morphology)
astrogliosis.
Astroglia and dementia
Dementia is the ultimate scourge of mankind, being generally
absent in every other animal species; and as such it may be
considered as the most appalling and horrible disease,
because it effectively robs human beings from their intelli-
gence and turns them into helpless entities. The causes of
dementia are many, ranging from traumatic injuries (mechan-
ical, chemical or as a result of irradiation) and viral infections,
which may predispose to dementia-related chronic neuro-
degenerative conditions, to the intrinsic neurodegenerative
processes associated with genetic factors, predispositions
and other yet unknown reasons. The pathological role of
astroglia in dementiae begun to be explored only very
recently; however, some generalisations can already be
drawn.
First and foremost, both astrogliosis and astroglial dystro-
phy are manifest in different types of dementia; furthermore,
both these processes may develop in parallel depending on
the disease form and/or stage. The frontotemporal dementias
(the clinical term covering several types of sporadic non-
Alzheimer cognitive disruptions, which include e.g., Pick’s
disease and frontotemporal lobar degeneration), is, for
example, associated with a very early and profound apoptotic
death and dystrophy of astrocytes.
41
The degree of astroglial
loss directly correlates with the severity of dementia.
Conversely, other study, using postmortem tissues from 21
frontotemporal dementia cases, found prominent astrogliosis
in the frontal and temporal cortices at the very early stages of
the disease, with astrocyte densities increasing by 4–5 times
of the control.
42
Astrogliosis also assumes the leading pathological role in
thalamic dementia (the rather rare form of specific dementia of
unknown aetiology). Numerous alterations of protoplasmic
astrocytes, manifested by highly localised proliferation of
perivascular and peryneuronal astroglial processes, believed
to be a primary pathological change, which can produce
dementia even without severe neuronal loss.
43
Similarly, in
HIV-1-associated dementia (HAD) significant astroglial hyper-
trophy and increase in GFAP (glial fibrillary acidic protein)
expression is observed in entorhinal cortex and hippocam-
pus.
44
Furthermore, there are indications that HIV-1 infected
reactive astrocytes, together with activated microglial cells,
may constitute a primary cause of neuronal damage, through
the release of various inflammatory and death factors.
45,46
At
the same time, however, HAD also leads to a prominent
apoptotic death of astrocytes especially in the patients with
rapidly progressing cognitive deficits.
47
Astroglia and Alzheimer’s disease
Alzheimer’s disease (AD), existing in both genetic (familial AD
or FAD) and sporadic forms,
48
is characterised by severe
neurodegeneration associated with an occurrence of specific
histopathological markers represented by focal extracellular
deposits of fibrillar b-amyloid (also called neuritic plaques) in
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Cell Death and Differentiation

brain parenchima and in the wall of blood vessels and
intraneuronal accumulation of neurofibrillary tangles com-
posed from abnormal hyperphosphorylated tau filaments. The
progression of AD is rather stereotypic with initial neurode-
generative events appearing in the transentorhinal cortex,
which afterwards spread to the entorhinal cortex and
hippocampus. Subsequently, the spreading wave of neuro-
degeneration swallows the rest of the temporal, frontal and
parietal lobes.
49,50
At the advanced stage of the AD, the grey
matter undergoes severe damage manifested by a profound
loss of neurones and synaptic contacts.
The pathological potential of glial cells in progression of
dementia (as well as in other types of brain pathology) was
originally suggested by Alois Alzheimer himself in 1910.
51
Many studies of the AD-related pathological potential of
astroglia have focused on the investigations of the effects of
b-amyloid on astrocytes. The treatment of cultured glial cells
with aggregated b-amyloid or with amyloid plaques isolated
from human AD brains triggered reactive astrogliosis.
52
In mixed astroglial-neuronal cultures b-amyloid peptide
(Ab 1–42) and its toxic fragment (Ab 25–35) provoked
sporadic increases and/or oscillations in cytosolic calcium
[Ca
2 þ
]
i
, which lasted for many hours.
53
These [Ca
2 þ
]
i
responses were observed solely in astrocytes and never in
neurones and were generated by Ca
2 þ
influx from extra-
cellular space, most likely through transmembrane channels
formed by Ab proteins. Importantly, astroglial [Ca
2 þ
]
i
fluctua-
tions were somehow linked to neuronal death, which occurred
24 h after Ab treatment; inhibition of Ca
2 þ
influx had a clear
neuroprotective effect.
53
In the AD human tissue the main astroglial reaction found
hitherto is represented by prominent astrogliosis, mostly
observed in the cells surrounding amyloid plaques.
54
Im-
portantly, activated astrocytes are capable of accumulating
large amounts of Ab;
55
the later being taken up by astrocytes
in association with neuronal debris. In addition, reactive
astrocytes seem to accumulate large amounts of neuronal
subtype of nicotinic cholinoreceptor (a7nAChRs), which is
known to have an exceptionally high affinity to b-amyloid.
Astroglial b-amyloid deposits are clearly associated with
plaques, as astrocytes positioned away from the plaques
show no b-amyloid burden.
54,55
Processes of activated
astrocytes were also reported to participate in plaques
formation.
54,55
At the very same time astroglial changes during AD
progression remain virtually unexplored. The main reason
for this is purely experimental as for many years the suitable
animal models for AD were absent.
Animal models of AD
Alzheimer’s disease, as every other dementia, is a sole
prerogative of humans; no animal suffers from AD.
56
Hence,
substantial efforts were invested in producing relevant animal
models of AD (for a comprehensive review of literature, see
references
57,58
). Initial models of AD were simply normal aged
animals,
59,60
which showed cholinergic involution associated
(in monkeys) with b-amyloid deposition.
61
As the AD is
manifested by a loss of cholinergic neurones,
62
several
cholinergic models of the disease were created. Among
these, the most relevant were the rodent models with lesions
in the nucleus basalis magnocellularis (nbm) that is the
equivalent of the nucleus of Meynert in humans.
56,63,64
These
models offered the possibility to investigate the differences in
structure, function and behaviour of the cholinergic systems in
young and aged animals.
63,64
The majority of these models,
however, were created by using non-selective excitotoxic
toxins such as NMDA, ibotenic acid, quisqualic acid and
certain alkaloid substances.
56
More refined lesion models
used more selective and specific toxins that affected only
cholinergic neurones in the relevant areas, such as septum,
nbm and the diagonal band of Broca, but preserved
non-cholinergic neurones.
56,65
These models were produced
by using AF64A cholinotoxin, which binds to the high affinity
choline uptake system, and 192 IgG-saporin that binds
selectively and irreversibly to low affinity nerve growth factor
receptor interrupting cholinergic neuronal protein synthesis.
Both these interventions lead to selective impairment and
death of cholinergic neurones.
None of the models mentioned above, however, mimicked
the histopathology (plaques and tangles) and progression of
AD. Therefore several experimental transgenic animals that
replicate various neuropathological features of AD have been
developed (see Table 1 and reference
58
). Initially, simple
transgenic models harbouring single-mutated b-amyloid-
related proteins (amyloid precursor protein (APP) or
presenilines, PS) or mutated tau were created. The very first
APP transgenic animal showing an AD-like pathology was
developed in 1995 by Games et al.
66
This model was called
PDAPP (single-transgenic mice expressing the ‘Swedish’ and
‘Indiana’ APP mutations Asp
664
to Ala (PDAPP(D664A)) and
showed many pathological features of AD, including extra-
cellular b-amyloid deposits, neuritic dystrophy, astrogliosis
and memory impairments, yet the latter did not correlate with
the degree of b-amyloid deposition.
58,66
Subsequently, Hsiao
et al.
67
developed the transgenic mice carrying APP
swe
mutation (Tg2576 mice) using a prion protein vector. These
animals had abundant Ab plaques as well as a memory and
learning impairment from 9 months of age. Subsequently, the
double-APP mutation, resulting the APP23 mouse was
created. This model showed a 14% loss of hippocampal
CA1 pyramidal neurons.
Mutations in PS proteins account for the majority of cases of
FAD.
58
To address the role of genetic risk factors in APP
Table 1 Summary of the transgenic AD animal models and the observed
neuropathology
Transgenic
mouse model Neuropathology Reference
APP
SWE
Plaques
68
PDAPP Plaques
69
APP
751SL
Plaques
70
PS1
M146L
Plaques
70
APP
SWE
/PS1
dE9
Plaques
71
APP/apoE-ko Plaques
72
TgCRND8 bAPP6
95
Plaques
73
APP
751SL
/PS1
M146L
Plaques
70
THY-Tau22 Tangles
74
Tau
P301L
Tangles
68
3xTg-AD Plaques and tangles
75
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processing and memory, double transgenic have been
created. Co-expression of PS1
dE9
with APP resulted in a
viable model that showed accelerated Ab deposition and
memory deficits without tangle formation.
71
Expression of
mutant APP on an ApoE knockout background did not affect
the age of onset of Ab plaques but instead of fibrillar Ab
mature plaques, only diffuse plaques were formed, suggest-
ing that ApoE affects fibrillogenesis and/or clearance of Ab.
76
The pathological tau animals were developed in parallel, the
first model being created in 1995;
77
these transgenic animals
showed somatodendritic localisation of hyperphosphorlation
of tau, but have not developed neurofibrillary tangle pathology
(NFT). After identification of the pathogenic mutations of tau in
FTDP-17, different transgenic models with clear neuronal
NFT were produced.
57,58
The Tau
P301L
(single-transgenic
mice expressing the Pro
301
to Leu tau mutation (P301L))
mutation is the most common associated mutation linked with
FTDP-17.
78
Transgenic mice overexpressing Tau
P301L
exhibit
neurofibrillary tangles without Ab pathology and/or neuronal
loss, except for the spinal cord (Table 1;
58,78
).
The triple-transgenic (3xTg-AD) AD animal model. One
of the most advanced AD animal models is represented by
the triple-transgenic mice developed in 2003 by Salvatore
Oddo and Frank LaFerla. These animals (the 3xTg-AD
mouse model) harbour the mutant genes for amyloid
precursor protein (APP
Swe
), for presenilin 1 PS1
M146V
and
for tau
P301L
.
75,79
These mice are recognised as relevant AD
model because they show temporal- and region-specific Ab
and tau pathology, which closely resembles that seen in the
human AD brain. As well as progressively developing
plaques and tangles, the 3xTg-AD animals also show clear
functional and cognitive impairments including LTP, spatial
memory and long-term memory deficits. These all are
Figure 1 Bar graphs showing the complexity (a) of glial cytoskeleton by measuring the GFAP area coverage versus volume ratio of within the molecular layer of the dorsal
dentate gyrus of both control and 3xTg-AD mice at different ages. (b and c) Bar graphs showing the coverage area (b) and volume (c) of GFAP at 12 months of age in control
and 3xTg-AD mice; *Po0.05 compared with age matching controls. (d and e) Fluorescence photomicrographs showing GFAP-positive cells in control (d) and 3xTg-AD mice
(e) at 12 months of age. There is an evident decrease in arborisation, surface area and volume in 3xTg-AD mice when compared with matching controls. All animal procedures
were performed according to the Animal Scientific Procedures Act of 1986 under the licence from the United Kingdom Home Office. The animals group were housed and kept
on daily 12 h light-dark cycles dark schedule. All mice were given ad libitum access to food and water
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manifest in an age-related manner; most importantly
functional deficits precede the appearance of histological
markers.
75,79
Cognitive deficits in the 3xTg-AD model
correlate with the accumulation of intraneuronal Ab.
80,81
It has to be noted, however, that all animal models of AD
developed so far have some limitations, the most serious one
being the absence of significant neuronal loss. This may
reflect some intrinsic differences between human and animal
brain, shorter lifespan of experimental animals or influence of
other yet unknown factors. At the same time absence of
neuronal loss in animals undergoing severe amyloidosis may
also question the toxic potential of neuritic plaques.
Glial atrophy and astrogliosis in transgenic AD
animals. We characterised morphology of astroglia in the
hippocampus of male 3xTG-AD mice using single and dual
immunohistochemical labelling.
82
For this labelling, we used
the antibodies to GFAP an astroglia cytoskeleton-specific
protein which expression varies between different brain
regions and is upregulated upon reactive astrogliosis, or
combined GFAP immunostaining with antibodies against
b-amyloid. Morphology of GFAP-positive astrolglial profiles
was reconstructed from series of optical confocal planes
taken from 50 mm thick fixed brain slices. After the
reconstruction of individual astrocytes the following
parameters were determined: surface area, volume and
cellular complexity (area versus volume; for the detailed
description of imaging/analysis techniques, see
references
83,84
).
Morphological characterisation of GFAP-positive astroglial
cells was performed on animals of different ages, from 3 to 12
months. To our surprise we found consistent reduction in the
GFAP expression (determined as surface and volume of
GFAP-positive profiles), which progressed with age. In very
young animals (3 months old), which did not have any signs of
AD pathology, astroglial morphology was already somewhat
altered. There was a slight reduction in astrocyte complexity
(by 1.29%; Figure 1a) that was directly associated with a
decrease in the number of processes and overall decrease in
both surface (12.62%) and volume (14.25%; data not shown)
of GFAP-labelled structures. Similar reduction in GFAP-
labelled profiles was observed at all ages, although this
decrease becomes significant only at 12 months of age. In
12-month-old animals the complexity was reduced by 5.04%
(P ¼ 0.0105; Figure 1a, d and e), whereas GFAP-positive
surface decreased by 38.99% and volume by 42.93%
(P ¼ 0.0211, 0.0292, respectively; Figure 1). On a cellular
level, this decrease in complexity was reflected by reduced
number of main processes and their arborisation (Figure 1c).
Incidentally, the same decrease in astrocytes complexity
was found in the postmortem brains of dementia patients. In
this study,
85
astroglial cells from neocortical area 11 were
Golgi impregnated and their complexity was characterised by
a fractal dimension. Astrocytes from adult and healthy aged
participants had similar complexity, whereas astrocytes from
patients with dementia showed significant decrease in fractal
dimension, thus indicating the decreased complexity. Further-
more, the volume of the brain parenchima occupied by the
processes of single astrocyte was smaller in demented brains.
At the very same time confocal images revealed that the
specific population of astrocytes surrounding amyloid plaques
display the typical reactive characteristics (Figure 2), showing
thick processes and enlarged cell bodies. Some of these
astrocytes closely associated with amyloid plaques showed
b-amyloid accumulation, as revealed by specific antibodies
(Figure 2b). Conversely, astrocytes positioned away from the
plaques did not show b-amyloid burden, which is consistent
with previous observations.
54,55
The 3xTg-AD animals show other changes that could be
associated with glial malfunction. For example, we observed a
transient increase in the number of asymmetric excitatory
synapses in AD mice at 2 months of age, which subsequently
dropped to control levels at 6–9 months. Nonetheless, this
increase in excitatory synaptic contacts re-emerged again at
12 months of age when the brain parenchyma was infested
with plaques, and neurones showed tangles.
86
In addition, we
Figure 2 Confocal image showing GFAP-positive (green) reactive astrocytes
surrounding b-amyloid plaques (red; a). (b) Reactive astrocytes (green) and an
astrocyte showing cytoplasmic b-amyloid accumulation (indicated by arrows;
colocalisation, yellow) near a neuritic plaque (red)
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also found significant decrease in the neurogenic capacity
of 3x-Tg-AD mice at 12 months of age,
87
which may reflect
degenerative changes in ‘stem-cell’-like astrocytes.
Astroglial theory of AD?
The pivotal role of astroglia in various types of brain pathology
is widely accepted.
6,88,89
Nevertheless, the pathological
potential of astrocytes in human dementias remains virtually
unexplored. From the scarce data available in the literature,
we may conclude that astrocytic reactions in various types of
dementia can be manifold, ranging from proliferation and
astrogliosis to apoptosis and dystrophy.
In AD, these two reactions develop in parallel and may
represent the underlying mechanism for loss in synaptic
connectivity and plasticity, which in turn determine cognitive
deficits. The reaction of astrocytes to the AD progression is
spatially distinct (Figure 3): astroglial cells surrounding the
plaques undergo gliosis, whereas astrocytes distant from the
amyloid deposits develop atrophy. The first signs of this
atrophy appear early in the genetic form of AD pathology in
mice; and these signs precede the formation of both plaques
and tangles. It is then conceivable to speculate that dystrophic
astrocytes fail to provide adequate support for synaptic
contacts, which may lead to their remodelling (e.g., distorted
balance between excitatory and inhibitory synapses), with
ensuing disruption of neuronal circuitry – and indeed the
synaptic loss is observed in early stages of AD when brain
parenchyma remains relatively free from neuritic plaques.
90,91
Furthermore, reduced astroglial coverage may significantly
affect extracellular brain homoeostasis. In particular, dys-
trophic astrocytes may have reduced ability for glutamate
uptake, thus increasing the overall brain vulnerability to
glutamate excitotoxicity. In contrast, the reactive astroglial
cells may serve another function – the function of neuronal
killers. Indeed, the main pillar of b-amyloid hypothesis of AD,
the toxicity of the neuritic plaques has been considerably
shaken by experiments on transgenic animals. The latter,
despite acquiring a heavy burden of amyloid plaques, show
very little (if any) neuronal death.
58
This discrepancy is
fundamental, as massive neuronal death assumes the main
role in the development of severe dementia in humans.
Naturally, the absence of neuronal extinction in the animal
model can be explained by a variety of reasons, yet it may also
hint that alternative mechanisms of the neurodegenerative
process are in operation. These mechanisms could be
Figure 3 Astroglial hypothesis of Alzheimer’s disease
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Cell Death and Differentiation

associated with both astroglial atrophy (reduced glutamate
uptake with increased glutamate excitotoxicity) and astro-
gliosis, as reactive astrocytes and activated microglia may
secrete numerous death-promoting molecules.
The AD, as well as other types of dementia, are complex
processes which engulf all cellular elements in the brain. Can
astrocytes assume the central stage in these pathologies?
This question requires further detailed and insightful
investigation.
Acknowledgements
. We thank the National Institute of Health, INTAS,
Alzheimer Research Trust UK and European commission for the grant support. AC
research was supported by the Grant Agency of the Czech Republic (nos. 305/06/
1316, 305/06/1464, 305/08/1384 and 309/08/1381), by the Ministry of Education,
Youth and Sports of the Czech Republic (nos. 1M0538 and LC554) and by the
Academy of Sciences of the Czech Republic (no. AVOZ50390512).
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