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available at www.sciencedirect.com

www.elsevier.com/locate/brainres

Research Report

Neuronal expression of vimentin in the Alzheimer's disease

brain may be part of a generalized dendritic
damage-response mechanism

Eli C. Levin a,b , Nimish K. Acharya a , Jonathan C. Sedeyn a , Venkateswar Venkataraman c ,

Michael R. D'Andrea d , Hoau-Yan Wang e , Robert G. Nagele b,⁎
a
University of Medicine and Dentistry of New Jersey/Graduate School of Biomedical Sciences, 2 Medical Center Drive, Stratford, NJ 08084, USA
b
New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey/SOM, 2 Medical Center Drive,
room 314, Stratford, NJ 08084, USA
c
Department of Cell Biology, University of Medicine and Dentistry of New Jersey/SOM, 2 Medical Center Drive, Stratford, NJ 08084, USA
d
Johnson and Johnson Pharmaceutical Research and Development, Spring House, PA 19477, USA
e
Department of Physiology and Pharmacology, The City University of New York Medical School, 138th Street and Convent Avenue,
New York, NY 10031, USA

A R T I C LE I N FO AB S T R A C T

Article history: Early pathological features of Alzheimer's disease (AD) include synaptic loss and
Accepted 20 August 2009 dendrite retraction, prior to neuronal loss. How neurons respond to this evolving AD
Available online 1 September 2009 pathology remains elusive. In the present study, we used single- and double-label
immunohistochemistry to investigate the relationship between neuronal vimentin
Keywords: expression and local brain pathology. Vimentin was localized to neuronal perikarya and
Alzheimer's disease dendrites in AD brain, with vimentin-immunopositive neurons prevalent in regions
Vimentin exhibiting intra- and extracellular beta-amyloid1-42 (Aβ42) deposition. Neuronal co-
Amyloid localization of vimentin and Aβ42 was common in the cerebral cortex, cerebellum and
Damage–response hippocampus. Additionally, neurons in affected brain regions of AD transgenic (Tg2576) mice
Dendrite and in brain tissue subjected to mechanical injury expressed vimentin, while those in
Synapse comparable regions of control mouse brain did not. Finally, we show that neurons in human
fetal brain express vimentin concurrently with periods of rapid neurite extension. Overall,
our results suggest that neurons express vimentin as part of an evolutionarily conserved,
damage–response mechanism which recapitulates a developmental program used by
differentiating neurons to establish dendrites and synaptic connections.
© 2009 Elsevier B.V. All rights reserved.

1. Introduction
Alzheimer's disease (AD) is the most common neurodegenera-
tive disorder and is characterized by progressive memory loss,
cognitive decline, behavioral changes, and eventual death
(Braak and Braak, 1991; Felician and Sandson, 1999; Mirra
et al., 1993; Sanders and Morano, 2008; Wisniewski et al., 1985).
Pathological hallmarks include neurofibrillary tangles, amyloid
deposits in cells and plaques, inflammation, synaptic loss, and
neuronal degeneration (Clifford et al., 2007, 2008; Dickson, 1997;

⁎ Corresponding author. Fax: +1 419 791 3345.

E-mail address: nagelero2009@gmail.com (R.G. Nagele).

0006-8993/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainres.2009.08.072
 BR A I N R ES E A RC H 1 2 9 8 ( 2 00 9 ) 1 9 4 –2 07 195

Fig. 1 – Vimentin is expressed in neurons in brain regions exhibiting typical AD pathology. (A) Low magnification view of the
cerebral cortex of an AD patient showing numerous vimentin-positive neurons. ast, astrocytes. (B) Higher magnification image
showing great variation in the intensity of vimentin immunoreactivity among pyramidal (Pyr) neurons. bv, blood vessel. (C, D)
Consecutive sections of the AD cerebral cortex with mild pathology immunostained with Aβ42 and vimentin, respectively.
Vimentin expressed by neurons burdened with intracellular Aβ42 (solid arrows). Consecutive sections of the cerebral cortex of
an AD brain with more advanced pathology showing intense vimentin immunostaining in many Aβ42-burdened neurons (E, F).
Open arrow, amyloid plaque. Bar = 100 μm.
196 BR A I N R ES E A RC H 1 2 9 8 ( 2 00 9 ) 1 9 4 –20 7

Glenner and Wong, 1984; Gomez-Isla et al., 1997; Grundke-Iqbal
et al., 1986; Hyman and Trojanowski, 1997; Mirra et al., 1991;
Rogers, 2008; Selkoe, 2002). Some of these pathological features
may precede the emergence of disease symptoms by years or
even decades (Blennow et al., 2006), and much evidence
suggests that synaptic loss is one of the earliest and most
important changes that occurs during AD pathogenesis (Selkoe,
2002). Synaptic loss is accompanied by dendrite retraction as
part of the early neuronal injury response, and both of these
changes are thought to make a major contribution to cognitive
and memory impairments observed in AD (Flood and Coleman,
1993; Marcello et al., 2008; Terry et al., 1991; Terry and Katzman,
2001). Thus, AD is considered to be primarily a disease of
synaptic failure (Marcello et al., 2008; Selkoe, 2002).
Early glial responses to AD pathology have been well-docu-
mented, particularly those involving astrocytes and their
dramatically increased expression of glial fibrillary acidic
protein (GFAP) (Hol et al., 2003; Nagele et al., 2004). Glial cells
can be activated in response to a variety of local neuropatho-
logical insults, and some can actively migrate to sites of paren-
chymal damage (Eng and Ghirnikar, 1994; Nagele et al., 2004;
Otsuka et al., 1991). Astrocytes can surround plaques and inter-
nalize amyloid (Funato et al., 1998; Nagele et al., 2003; Otsuka
et al., 1991). In AD brain regions exhibiting neuronal loss,
microglia are also activated and become engaged in debris-
clearing, largely via phagocytosis (Nagele et al., 2004; Shaffer
et al., 1995; Streit et al., 2008). Whether central nervous system
(CNS) neurons also have a damage–response mechanism that
may aid in synaptic repair has not been clearly established,
though it has been suggested that damaged neurons may
demonstrate capacities resembling differentiating neurons
(Aguayo et al., 1991). Indeed, such a response could conceivably,
at least in part, account for the rather long delay between the
onset of AD pathology and the appearance of symptoms.
We have investigated the possibility that neurons elicit a
dendrite and synaptic repair mechanism during AD pathogen-
esis that includes a recapitulation of the fetal mechanism that
generated the initial dendrite branching and synaptic dis-
tribution patterns during development. As a first effort to
study and characterize such a phenomenon, we have begun to
investigate the re-expression of developmental proteins in
neurons of AD brains. One such protein appears to be
vimentin. Vimentin is 57 kDa intermediate filament (IF)
protein found primarily in cells of mesenchymal origin
(Franke et al., 1979b, 1982; Paulin et al., 1982). It is widely
expressed in embryos and is often later replaced by the other
major classes of IFs in cells during terminal differentiation
(Bignami et al., 1982; Boyne et al., 1996; Cochard and Paulin,
1984; Franke et al., 1982). In the developing CNS of the chick
and rodents, vimentin is expressed by virtually all cells within
the proliferative neuroepithelium, including neuronal precur-
sors where expression is necessary for neurite extension, as a
component of cytoskeletal assembly (Bignami et al., 1982;
Cochard and Paulin, 1984; Houle and Fedoroff, 1983; Tapscott
et al., 1981). In the healthy adult brain, vimentin expression is
largely restricted to vascular endothelial cells and certain
subpopulations of glial cells (Bignami et al., 1982; Franke et al.,
1979a; Izmiryan et al., 2009). In AD brains, both protoplasmic
and fibrous astrocytes express vimentin in regions of AD
pathology (Yamada et al., 1992). Finally, a protein that
comigrates with vimentin was reported in association with
neurofibrillary tangles, suggesting that neurons may re-
express vimentin in AD brains (Yen et al., 1983).
In the present study, immunohistochemistry (IHC) was
employed to examine the presence and distribution of
vimentin within the brains of AD patients and age-matched
controls. Our results establish the presence of vimentin in
neuronal cell bodies and their processes in AD brain but not in
comparable regions of control brains. Neuronal expression of
vimentin was most prevalent in the dendrite compartment of
neurons, with a good correlation to the extent of local
pathology. This relationship was also confirmed in AD
transgenic mice as well as in adult mouse brains subjected
to mechanical damage. Our results support the notion that
vimentin expression in AD brains is a key component of a
neuronal damage–response mechanism that recapitulates the
process used by differentiating neurons to extend and
establish their dendrites and synaptic connections.
2. Results
The presence and distribution of vimentin in human and mouse
brain tissues were investigated using IHC and vimentin-specific

Table 1 – Relationship between neuronal vimentin expression, intraneuronal Aβ42 deposition and amyloid plaque (AP)
density.
Disease severity AP density (/mm2) Aβ42-positive neurons Vimentin-positive neurons

Total neurons Total neurons

Control 0 12.5 (304/2428) 10.4 (221/2135)

Mild AD 3.8 33.5 (692/2066) 23.8 (493/2073)
Severe AD 26.3 60.7 (1264/2083) 62.4 (1349/2162)

Pyramidal cells Pyramidal cells

Control 0 4.4 (31/704) 2.5 (17/687)

Mild AD 3.8 78.5 (443/564) 72.2 (397/550)
Severe AD 26.3 84.9 (643/757) 78.7 (551/700)

Note. All values for vimentin- and Aβ42-positive neurons are derived from immunohistochemistry of consecutive sections and are given as
mean of the percentage of total neurons counted. At least four viewing fields were used for each data point. Data are from the cerebral cortex of
four AD (two mild and two severe) and two age-matched control brains.
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Fig. 2 – Neurons express vimentin in several AD-relevant brain regions. (A, B) Consecutive sections of AD cerebellum showing
vimentin localized to the perikaryon and main dendrite trunk of Aβ42-immunopositive Purkinje neurons. (C, D) Consecutive
sections showing localization of neuronal vimentin to the perikaryon and especially the dendrites of neurons in the AD
hippocampus, with confirmation of dendrite location via MAP2 immunostaining. bv, blood vessel. (E) Section of AD cerebral
cortex showing intense vimentin immunostaining of pyramidal neurons. (F) Section of cerebral cortex of age-matched control
brain showing vimentin expression restricted to blood vessels. Bar = 100 μm.
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antibodies. Four different anti-vimentin antibodies (see Experi-
mental procedures for details) were tested and compared. The
specificity of each antibody for vimentin was confirmed by
western analysis (data not shown). Three of the four antibodies
were found to detect vimentin expression in neurons, with the
Sigma V9 antibody showing the greatest immunoreactivity and
selected for the work presented here.
2.1. Vimentin is expressed preferentially in the perikaryon
and dendrite compartments of neurons in brain regions
exhibiting AD-related pathology
Examination of low magnification views of the cerebral cortex
of AD brains immunostained with anti-vimentin antibodies
revealed the presence of many vimentin-positive neurons
(Fig. 1A). The subset of cortical neurons consistently exhibiting
the most intense vimentin expression were large pyramidal
neurons positioned in the deeper cortical layers (e.g., cortical
layers 4–6) (Fig. 1B). Interestingly, these neurons showed great
variation in the intensity of vimentin immunostaining, ranging
from little or no detectable staining to intense immunostaining
in the perikaryon and extending into the main apical dendrite
trunk (Figs. 1A and B). Both the relative number of local neurons
exhibiting vimentin expression and the intensity of their
vimentin-specific immunolabeling was related to the severity
of local pathology (Figs. 1C–F, Table 1). Here, we judged the
severity of local pathology by comparing the relative numbers
of neurons with intraneuronal beta-amyloid (Aβ42), the local
density of amyloid plaques and neurofibrillary tangles, and the
degree of inflammation via detection of activated, HLA-dr-
immunopositive microglia (HLA-dr and tangle data not shown).
In contrast to AD brain, age-matched control cortex contained
no amyloid plaques and few Aβ42 positive neurons (data not
shown). In cortical regions showing mild to moderate AD
pathology, vimentin expression by neurons was highly variable
but often robust (Figs. 1A–D). In contrast, regions with more
severe pathology generally showed a similar level of overall
vimentin expression, a result of neuronal loss neutralizing an
increased percentage of vimentin immunostaining in remain-
ing neurons (Figs. 1E–F, Table 1).
Vimentin expression was also detected in neurons in other
AD-relevant brain regions including the cerebellum, hippo-
campus, and entorhinal cortex (Figs. 2A, C, and E). Immunos-
taining of consecutive histological sections of cerebellum from
AD patients with Aβ42 and vimentin-specific antibodies
revealed robust expression of vimentin in Aβ42-immunopo-
sitive Purkinje neurons and their main dendrite trunks
(Figs. 2A and B). A similar preferential localization of neuronal
vimentin in the perikaryon and dendrites was noted in the AD
hippocampus (Fig. 2C), with microtubule-associated protein-2
(MAP2) immunostaining confirming the location of the
dendrite arbors (Fig. 2D). In age-matched control brains,
detection of vimentin-positive neurons was rarely in evidence
(Fig. 2F, Table 1) and was restricted to focal sites showing some
signs of early AD-like pathological changes (data not shown).
MAP2 controls, which received no primary antibody, showed
no immunostaining of any kind (data not shown). In both AD
and control brains, vascular endothelial cells were consis-
tently vimentin-immunopositive (Figs. 2A, C, E, and F).
Astrocytes positioned within the molecular layer of the cortex
were often intensely vimentin-immunopositive (Fig. 1A),
while those in the underlying pyramidal cell layers of the
cortex were generally negative for vimentin (Fig. 1B), though
with some notable exceptions (Fig. 1F).
2.2. Vimentin is expressed by neurons in AD brain regions
exhibiting intraneuronal and extracellular Aβ42 deposition
A well-known pathological hallmark of AD brains is the
deposition of beta-amyloid, especially Aβ42, within neurons,
amyloid plaques, and the walls of blood vessels [referred to as
cerebral amyloid angiopathy (CAA)]. To investigate a possible
relationship between intracellular Aβ42 deposition in AD
brains and neuronal vimentin expression in the same neurons,
we carried out double-immunostaining of histological sections
of brain tissue with antibodies against vimentin and Aβ42
(Figs. 3A–F). Quantitation of double-stained AD brains showing
mild pathology revealed that roughly half of all pyramidal
neurons [52.4% (160/305 cells)] were Aβ42-positive. In AD brain
regions showing mild pathology (i.e., with significant intra-
neuronal Aβ42 accumulation but few amyloid plaques),
vimentin expression occurred in nearly all neurons [98.1%
(157/160 cells)] containing intracellular Aβ42 deposits (Figs. 3A,
B, and E), suggesting that intraneuronal Aβ42 accumulation
may trigger vimentin expression in adult neurons in AD brains.
Vimentin was also expressed by neurons lacking substantial
intracellular Aβ42 deposits [86.9% (126/145 cells)] when they
were positioned in the vicinity of amyloid plaques (Figs. 3C–E).
In AD brains with more advanced pathology (fewer viable
neurons, large intraneuronal Aβ42 deposits and a higher
density of amyloid plaques), neuronal vimentin expression
was essentially universal though appeared spatially restricted
to the portion of the perikaryon not occupied by intracellular
Aβ42-immunopositive deposits (Fig. 3F).
2.3. Vimentin is expressed in adult mouse brain neurons
in response to experimentally-induced injury
A primary feature of AD progression underlying the presenta-
tion of classical symptoms is the rampant loss of synapses and
the associated degeneration of dendrites. As described above,
we have observed the selective expression of vimentin in
neurons in brain regions exhibiting AD pathology. The localiza-
tion of vimentin in the main dendrite trunks of neurons raised
the possibility that expression of vimentin may represent part of
a neuronal repair mechanism in response to local synaptic loss.
To test this possibility, we subjected adult mouse brain tissue to
mechanically-induced damage caused by brain slicing, such as
that commonly used for the preparation of hippocampal slice
cultures. In control brain slices, those fixed immediately after
slicing (n = 9), neurons generally lacked detectable vimentin
expression [0.4% (2/438 cells)], though vimentin was observed in
the endothelium of blood vessels (Fig. 4A). However, when brain
slices were instead incubated in medium for 3 (n = 9) or 16 h (n = 9)
following slicing, neurons in the cerebral cortex [82.8% (236/285
cells)] exhibited abundant vimentin expression in their peri-
karya and main dendrite trunks (Figs. 4B–D). Taken together,
these results indicate that vimentin expression by neurons and
its localization in dendrites occurs in response to dendrite
damage.
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Fig. 3 – Vimentin is expressed by neurons in AD brain regions exhibiting intracellular and extracellular amyloid. Sections were
double-immunostained for vimentin (red) and Aβ42 (blue). (A) Low magnification view of AD brain region showing relatively
mild pathology and intense vimentin expression in neurons containing intracellular Aβ42. bv, blood vessel with CAA. (B)
Enlarged portion of “A” highlighting intracellular Aβ42 deposits and vimentin in pyramidal (Pyr) neurons. (C, D) Vimentin
expression in neurons in AD cerebral cortex lacking substantial intracellular Aβ42 deposits. (E) Section showing vimentin
localized to the perikaryon and main dendrite trunk, but not axons, of cortical pyramidal neurons. Arrows, intracellular Aβ42
deposits. (F) Section of AD brain with more advanced pathology showing vimentin expression restricted to dendrites.
Bar = 25 μm.
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2.4. Vimentin is expressed by neurons in AD transgenic
(Tg2576) mouse brains
The Tg2576 mouse is one of the most commonly used animal
models for studying AD pathogenesis (Duff and Suleman,
2004; Hsiao et al., 1996). Although many of these models do not
show the same level of neuronal loss seen in AD brains, these
models do exhibit significant synaptic loss and amyloid
deposition within the brain tissue, including some late-stage
plaque formation (Dong et al., 2007; Irizarry et al., 1997). The
apparent linkage of vimentin expression and neuronal
damage described above led us to test for neuronal vimentin
expression in histological sections of AD transgenic (Tg2576)
mouse brain (n = 4). Results showed that many neurons [33.0%
(236/285 cells)] were immunopositive for vimentin (Figs. 4E
and F). Interestingly, as in AD brains showing mild AD
pathology (cf. Figs. 1A and B), pyramidal neurons in the
cerebral cortex showed considerable variation in the intensity
of vimentin immunostaining, ranging from no detectable
staining to a rather intense immunostaining (Figs. 4E and F).
2.5. Vimentin is expressed in neurons undergoing
neuronal differentiation and neurite extension in the human
fetal brain
The findings described above suggest that vimentin expres-
sion in neurons and its localization in the dendrite compart-
ment may be part of a neuronal response mechanism to local
tissue damage or to damage imposed on the neuron itself. In
view of previous studies that have demonstrated neuronal
vimentin expression during development in rodent and chick
models (Bignami et al., 1982; Cochard and Paulin, 1984; Franke
et al., 1982; Tapscott et al., 1981), we examined neurons in
human fetal brain for vimentin expression. As shown in Fig. 5,
neurons in the cerebral cortex of human fetal brain are
intensely vimentin-immunopositive, with vimentin localized
to the perikaryon and dendrites (Fig. 5). Vimentin expression
in dendrites of human fetal neurons extended into their finer
branches (Figs. 5A and B). This suggests that expression of
vimentin in neurons during development may be related to
establishment of initial dendrite branching patterns and
synaptic connections.
3. Discussion
In the present study, we show that vimentin is expressed in
the perikaryal and dendritic compartments of mature neurons
in the adult brain in response to local cellular and tissue
damage arising from trauma and/or disease. We propose that
this expression represents part of an evolutionarily conserved,
inherent neuronal damage–response mechanism aimed at
repairing defective or damaged dendrite trees and their
associated synaptic connections.
Vimentin is a 57-kDa intermediate filament (IF) protein
commonly found in mesodermally derived cells (Evans, 1998;
Franke et al., 1982). In the healthy adult brain, vimentin is
lacking in neurons and generally restricted to vascular
endothelial cells and certain subpopulations of glial cells at
specific brain locations (Bignami et al., 1982; Boyne et al., 1996;
Cochard and Paulin, 1984; Franke et al., 1982). Exceptions are
the neurons comprising the proliferative olfactory epithelium
and horizontal cells of the retina, which express vimentin
throughout life (Ho and Liem, 1996; Schwob et al., 1986). By
contrast, vimentin expression in neurons appears to be more
commonplace during development. For example, in the
developing CNS of the chick and rodent, vimentin is expressed
by both neuronal and glial cellular precursors within the
proliferative neuroepithelium (Bignami et al., 1982; Cochard
and Paulin, 1984; Houle and Fedoroff, 1983; Tapscott et al.,
1981). In embryos, vimentin expression in neurons has been
shown to precede and then later be replaced by the appear-
ance of the major neurofilament proteins during neuronal
maturation and neuronal process extension and is necessary
for process extension (Bignami et al., 1982; Boyne et al., 1996;
Cochard and Paulin, 1984; Franke et al., 1982). Vimentin is
detected in differentiating mouse neurons during embryonic
days 9 through 12, a period of active dendrite and axon
extension, and thereafter is replaced by neurofilaments
(Cochard and Paulin, 1984). Similar vimentin expression
patterns have been described during in vitro neuronal devel-
opment (Bignami et al., 1982; Cochard and Paulin, 1984). In
addition, we show here that vimentin is abundantly expressed
in cerebral cortical neurons in human fetal brain tissue. Taken
together, these observations support that vimentin may be
required in the fetus for initiation, extension and branching of
developing dendrite trees (Boyne et al., 1996).
3.1. Neurons express vimentin in response to local
cellular/tissue damage in AD brains and transgenic (Tg2576)
mouse brains
Many years ago, Yen et al. (1983) described the detection of
vimentin or a vimentin-like protein in association with
neurofibrillary tangles in AD brains and suggested that
neurons may be re-expressing this protein in response to AD
pathology. The results of the present study show that
vimentin expression is much more widespread in AD brains
than previously thought, and demonstrate a temporal and
spatial relationship between neuronal vimentin expression
and an evolving local AD pathology. We have found that, in AD
brains, vimentin is localized preferentially in the perikaryal
and dendritic compartments of neurons. This was observed
predominantly within or near brain regions exhibiting the
classical micropathological features of AD pathology (e.g.,
intraneuronal amyloid accumulation, amyloid plaques and
neurofibrillary tangles). Large pyramidal neurons in the
frontal, temporal and entorhinal cortices showed the most
robust vimentin expression, but vimentin-immunopositive
neurons were also observed in other AD-vulnerable brain
regions including the hippocampus and cerebellum. On the
other hand, vimentin-immunopositive neurons were rare in
age-matched control brains, and these were restricted to
regions exhibiting AD-like pathological features. Likewise, we
found that neurons in the brains of AD transgenic (Tg2576)
mice also express vimentin within their perikarya and main
dendrite trunks. As in AD brains exhibiting mild AD pathology,
pyramidal neurons in the cerebral cortex of Tg2576 mouse
brains showed considerable individual variation in the
intensity of vimentin immunostaining.
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Fig. 4 – Vimentin is expressed in neurons in adult mouse brain neurons in response to experimentally induced injury and in
AD transgenic (Tg2576) mice. (A) Section of mouse brain fixed immediately after slicing (control) showing lack of vimentin
expression in pyramidal (Pyr) neurons. bv, blood vessels. (B) Section of brain maintained for 3 h in culture medium after
slicing showing vimentin localized to the perikarya and main dendrite trunks of cortical pyramidal neurons. (C, D) By 16 h
post-slicing, most neurons in the hippocampus (C) and cerebral cortex (D) show robust vimentin expression. Arrows,
corkscrew dendrites indicative of dendrite retraction. (E, F) Sections of cerebral cortex from AD transgenic (Tg2576) mouse
showing many vimentin-immunopositive pyramidal neurons. Bar = 25 μm.
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Fig. 5 – (A, B) Vimentin is prominent in differentiating neurons of the human fetal brain. Neuronal perikarya, main dendrite
trunks and their finer branches are all vimentin-positive. Endothelial cells of blood vessels (bv) also express vimentin.
Bar = 25 μm.

During the past two decades, a number of useful transgenic
mouse models have been widely used to investigate mechan-
isms of AD pathogenesis (Duff and Suleman, 2004). The
specific pathological features that arise in these models vary
considerably among the different transgenic models.
Although none of these models show the same degree of
neuronal loss and amyloid deposition seen in advanced AD
brains, most display significant synaptic loss and amyloid
deposition (Dong et al., 2007; Irizarry et al., 1997). In many
respects, the level of pathology achieved in some AD
transgenic mouse models appears to be consistent with that
commonly observed in brains of patients showing mild
cognitive impairment. The fact that neuronal vimentin
expression is commonly observed in the brain at relatively
early stages of disease progression suggests that neuronal
repair, including vimentin expression, may initiate long before
patients present for evaluation of possible dementia. In
addition, it is interesting to note that neurons in both
human and mouse brain express vimentin in response to
damage or disease, suggesting that this response may be
evolutionarily conserved among mammals.
3.2. Neuronal vimentin expression is linked to intracellular
amyloid deposition and the local presence of amyloid plaques
Using both double-label and consecutive section immunohis-
tochemistry, we have demonstrated abundant vimentin
expression in the perikaryon and main dendrite trunks of
neurons containing large intracellular Aβ42 deposits. Similar
expression was discovered in neurons lacking substantial
intracellular Aβ42 that were positioned in the vicinity of
amyloid plaques. These findings suggest a positive correlation
between the nature and extent of local amyloid deposition in
AD brains and neuronal vimentin expression. In AD brain
regions showing more advanced pathology, there was a
tendency for vimentin expression to be spatially restricted to
a small portion of the perikaryon and main dendrite trunk.
This was apparently due to the presence of relatively large
intracellular Aβ42-containing deposits occupying most of the
cytoplasmic volume. It is well known that the integrity and
maintenance of the finer branches of neuronal dendrite trees
and their associated synaptic connections are heavily depen-
dent on the synthesis and delivery of proteins produced in the
perikaryon (Sala et al., 2008). In view of this, it is reasonable to
expect that the intraneuronal accumulation of beta-amyloid
and its sequestration into large aggregates in the perikaryon
may compromise the ability of affected neurons to materially
support their dendrite trees. Here we suggest that, in Aβ42-
burdened neurons, the observed vimentin expression may be
related to the neuron's attempt to repair or re-grow defective
dendrite branches. Further studies attempting to modulate
the expression of vimentin in neurons under conditions of
tissue damage and/or disease will be necessary to determine if
this is the case.

Fig. 6 – Proposed model for the role of vimentin in neuronal damage–response. An initial pathological event occurs, causing
rapid damage to the neuron resulting in synaptic disruption and dendrite retraction. Over the course of several hours to several
days, the neuron responds by expressing and transporting vimentin to the damaged dendrite. As long as the damage is not
chronic, the neuron is able to reestablish its dendritic tree over the course of several weeks to several years. Vimentin
expression is then turned off and the neuron resumes its normal function. If the damage is chronic, or if the initial damaging
event is too severe, the neuron will be unable to reestablish its lost synaptic connections and it will either remain impaired or
eventually die.
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3.3. Neurons express vimentin in response to
traumatic injury
Although direct evidence for the existence of a neuronal
repair mechanism early in AD pathogenesis is scant, some
reports have described regrowth of dendrites and synapses
in AD brains subsequent to synaptic loss (Cotman and
Anderson, 1988; McKee et al., 1989). As detailed above, our
results show that neurons express vimentin concurrent with
the evolving pathology in the brains of AD patients and AD
transgenic mice. Furthermore, these findings suggest that
the response is a key component of dendrite and synapse
repair. These outcomes have raised the question of whether
vimentin expression is routinely implemented by neurons in
response to different types of tissue damage, including brain
trauma. We tested this possibility by subjecting adult mouse
brain tissue to mechanically induced damage caused by
brain slicing. Brain slicing inevitably results in variable
degrees of dendrite and axonal damage depending on the
specific location and orientation of neurons relative to the
plane of the cut. We found that, immediately after slicing,
neurons generally lacked detectable vimentin expression.
However, when cells in brain slices were allowed to recover
for 3–16 h in culture, many neurons in the cerebral cortex
and hippocampus exhibited abundant vimentin expression.
These results suggest a more direct relationship between
physical damage to the dendrite and the expression of
vimentin within affected neurons. In addition, our findings
are also in accord with the concept that vimentin is
expressed by neurons as part of a common neuronal
damage–response mechanism that is implemented regard-
less of the cause of that damage.
3.4. Perspectives
Much evidence now supports the concept that AD is largely
a disease of synaptic loss and that this loss may be initiated
a number of years before the emergence of detectable
symptoms (Davies et al., 1987; Marcello et al., 2008; Selkoe,
2002; Terry et al., 1991). The apparently long span of time
between the initiation of pathology and the arrival of the
patient for evaluation and treatment implies that a neuro-
nal repair mechanism may operate during this interval to
counteract synaptic loss and ward off the expression of
detectable symptoms. A proposed model for the role of
vimentin in the neuronal damage–response mechanism is
shown in Fig. 6. Our data presented here suggest that
neurons express vimentin as part of a mechanism aimed at
repairing degenerating dendrites and their lost synapses.
Furthermore, we suggest that damaged mature neurons
may be recruiting an existing default mechanism for neurite
extension that was previously used by these neurons during
terminal differentiation and establishment of initial den-
drite branching patterns and synaptic connections. The
observed widespread expression of vimentin in developing
neurons in the CNS of embryos and fetuses observed by us
and others support this possibility. As more is learned about
this mechanism and its contribution to the repair of
dendrites and synapses, novel therapeutic targets may be
elucidated.
4. Experimental procedures
4.1. Antibodies
Aβ42 antibodies were obtained from Chemicon International
(Temecula, CA) (mouse polyclonal, Cat. No. AB5078P, dilu-
tion = 1:50) and Pharmingen (San Diego, CA) (polyclonal Cat.
No. 4767, dilution = 1:50). Vimentin antibodies were obtained
from Sigma (St. Louis, MO) (monoclonal, Cat. No. V6630,
dilution = 1:200), Santa Cruz (Santa Cruz, CA) (polyclonal, Cat.
No. sc7557, dilution = 1:50), Chemicon-Millipore (Temecula,
CA) (monoclonal, Cat. No. mab3400, dilution = 1:1000), Dako
(Glostrup, Denmark) (monoclonal, Cat. No. U7034, dilu-
tion = 1:25). Microtubule-associated protein 2 (MAP2) anti-
body was obtained from Chemicon (monoclonal, Cat. No.
mab3418, dilution = 1:500). The specificity of each of these
antibodies was confirmed by western blotting or ELISA (data
not shown).
4.2. Animals
C57BL/6J mice were obtained from Jackson Laboratories (Bar
Harbor, ME); C57 × SJL and AD transgenic (Tg2576) mice were
obtained from Taconic (Hudson, NY) and used at 3–6, 3–6, and
9 months of age, respectively. Mice were maintained on ad
libitum food and water with 12-h light/dark cycle in an
AAALAC-accredited vivarium.
4.3. Mouse brain slice cultures
Brains were removed from C57BL/6 mice (n = 9) and cut (0.5-
mm thick) using a tissue chopper and placed in medium (25%
inactivated horse serum, 25% Hanks' BSS, 50% DMEM, 25 mg/l
penicillin–streptomycin) (Invitrogen, Carlsbad, CA) in six-well
culture dishes for 0–16 hr at 37 °C in a 5% CO2-enriched
atmosphere. Brain slices were fixed with 4% paraformalde-
hyde (PFA) in PBS at room temperature and processed for
immunohistochemistry as described below.
4.4. Human brain tissue
Brain tissue from patients with sporadic AD (n = 16, age
range = 71–87) and age-matched, neurologically normal indivi-
duals (n = 9, age range = 69–81) were obtained from the Harvard
Brain Tissue Resource Center (Belmont, MA), the Cooperative
Human Tissue Network (Philadelphia, PA), the UCLA Tissue
Resource Center (Los Angeles, CA) and Slidomics (Cherry Hill,
NJ). Post-mortem intervals were < 24 h and pathological
confirmation of AD was evaluated according to the criteria
defined by the National Institute on Aging and the Reagan
Institute Working Group on Diagnostic Criteria for the Neuro-
pathological Assessment of AD (Hyman and Trojanowski,
1997). Tissues were characterized immunohistochemically for
the presence of amyloid plaques and neurofibrillary tangles as
described previously (Nagele et al., 2002). Control tissues
exhibited no gross pathology and minimal localized micro-
scopic AD-like neuropathology. Tissues were processed for
routine paraffin embedding and sectioning according to
established protocols. Human fetal brain tissue was obtained
 BR A I N R ES E A RC H 1 2 9 8 ( 2 00 9 ) 1 9 4 –2 07
from archived fixed and paraffin-embedded tissues derived
from the Southern New Jersey Fetal Loss Project with research
consent and approval from UMDNJ's IRB.
4.5. Mouse brain tissue
Mice were sacrificed and brains were quickly isolated and
fixed with 4% PFA in PBS for 2 h. Using a tissue slicer, the brain
was cut into 1-mm slabs and fixation was continued in 4% PFA
overnight. The brain tissue was then infiltrated with 10%
sucrose in PBS for 2 h, followed by 30% sucrose in PBS
overnight at 4 °C under constant gentle agitation. Using a Leica
cryostat, 12-μm-thick frozen sections were cut, mounted onto
Fisher Super Frost Plus slides, and air dried.
4.6. Immunohistochemistry
Immunohistochemistry for paraffin-embedded tissues was
carried out as previously described (D'Andrea et al., 2001;
Nagele et al., 2002). Briefly, tissues were deparaffinized using
xylene, rehydrated through a graded series of decreasing
concentrations of ethanol. Protein antigenicity was enhanced
by microwaving sections in citrate buffer. Frozen sections
were immersed in acetone for 2 min and air dried. Endo-
genous peroxidase was quenched by treating sections with
0.3% H2O2 for 30 min. Sections were first incubated in block-
ing serum and then treated with primary antibodies at ap-
propriate dilutions for 1 h at room temperature. After a
thorough rinse in PBS, biotin-labeled secondary antibody was
applied for 30 min. Sections were treated with the avidin–
peroxidase-labeled biotin complex (ABC, Vector Labs, Foster
City, CA) and visualized by treating with 3-3-diaminobenzi-
dine-4-HCL (DAB)/H2O2 (Biomeda, Foster City, CA). Sections
were then lightly counterstained with hematoxylin, dehy-
drated through increasing concentrations of ethanol, cleared
in xylene and mounted in Permount. Controls consisted of
brain sections treated with non-immune serum or omission
of the primary antibody. Specimens were examined and
photographed with a Nikon FXA microscope, and digital
images were recorded using a Nikon DXM1200F digital camera
and processed using Image Pro Plus (Phase 3 Imaging, Glen
Mills, PA) image software.
4.7. Quantitation of neuronal vimentin expression and
amyloid plaque (AP) density
Vimentin- and Aβ42-positive neurons and APs were counted
in consecutive sections of cerebral cortex from AD and age-
matched control brains. Images were optimized and count-
ing was performed using the counting feature of Adobe
Photoshop CS3. At least four viewing fields within the
cortical pyramidal cell layers of AD and control brains were
counted. Only neurons showing nuclei in the section plane
were included. Cells were considered vimentin- and Aβ42-
positive if they showed immunostaining in the cell body
and/or main apical dendrite. The percentage of total neurons
immunopositive for vimentin and Aβ42 in AD and age-
matched control brains and vimentin-immunopositive neu-
rons in the cerebral cortex of transgenic (Tg2576) mice and
in slices of adult mouse brain (mechanical damage) and
205
their appropriate controls were determined. To reveal the
relationship between the presence of intracellular Aβ42 and
vimentin expression in the same neuron, sections subjected
to double-label immunostaining were also evaluated. APs
larger than 10 μm were counted in each field and data was
presented as AP density (number of plaques per square
millimeter of the tissue section). Means were determined for
each data set.
Acknowledgments
This work was supported by the Alzheimer's Association, the
NJ Governor's Council on Autism, the New Jersey Commission
on Science and Technology, and the Foundation of UMDNJ.
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