Pathogenesis of vascular dementia
Transcript of Pathogenesis of vascular dementia
esentations P4 S705
P4-020 HYPERPHOSPHORYLATION ALONG THE
Poster Pr
C-TERMINAL OF TAU PROTEIN IS ASSOCIATED
WITH PHFASSEMBLY RESULTING FROM
TRUNCATION AT GLU-391, IN ALZHEIMERA�S
DISEASE
Jos�e Luna-Mu~noz1, Paola Flores1, Sergio Zamudio Zamudio2, Fidel De la
Cruz De la Cruz2, Charles R Harrington3, Claude M. Wischik3,
Ra�ul Mena L�opez4, 1CINVESTAV-IPN, DF, Mexico; 2IPN, DF, Mexico;3University of Aberdeen, Aberdeen, United Kingdom; 4CINVESTAV, DF,
Mexico.
Background: Hyperphosphorylated and truncated species of tau molecule
are characteristically found in the paired helical filaments (PHF) which
are found in Alzheimer’s diseased brains. A causal relationship between
those two events has not been determined yet. After the neuronal death,
the intracellular neurofibrillary tangle (NFT) is eventually released into
the extracellular space becoming a ghost tangle. This structure is character-
istically identified by themonoclonal antibody 423 which was raised against
a fragment of tau protein which carries a C-terminal truncation at Glu-391
(Novak et al. Embo J, 1993. 12: 365-70). This truncated tau protein repre-
sents the so called PHF-core, which is characteristically stable and highly
insoluble. By in vitro studies, it has demonstrated that the PHF core is highly
toxic by inducing apoptosis. Objective. To determine the relationships be-
tween C-end hyperphosphorylation and Glu391 truncation at early stages
of PHF assembly. Methods: This study was based on double and triple
immunolabelling using 423, S396, S400, S404, S409 AD2, S422, counter-
stained with Thiazin red (TR) (Acta Neuropathol, 1996. 91: 633-41). Slides
were analized using confocal microscopy. Results: The immunoreactivity
of all phospho-dependent tau antibodies, excepting S422, was found coloc-
alizing with TR in the forms of beads or small tangles in the proximal neu-
ronal processes As expected, E-NFTwere detected by 423. Interestingly, the
phospho-dependent tau marker, S396, was also found in the latter structures.
Conclusions: This study suggests that the phosphorylation tau protein pro-
cessing results as a consequence of the appearance of the PHF core. In gen-
eral, this confocal analysis indicates that hyperphosphorylation processing
along the C-portion of tau protein is a protective response to toxicity pro-
duced by the appearance of the PHF core fragments, whose exposure leads
to tau protein assembly into PHF.
P4-021 SMOKING ACELERATES AMYLOID FORMATION
AND ASSOCIATED NEURODEGENERATIVE
ALTERATIONS IN ATRANSGENIC MOUSE
MODEL OFALZHEIMERA�S DISEASE
Ines Moreno-Gonzalez1, Lisbell D Estrada2, Claudio Soto3, 1University of
Texas - Health Science Center at Houston, Houston, Texas, United States;2Universidad Catolica de Chile, Santiago, Chile; 3University of Texas
Houston Medical School, Houston, Texas, United States.
Background: Several epidemiological studies have shown that cigarette
smoking might alter the incidence of AlzheimerA�s disease (AD). However,
some studies have reported an increase and others a decrease on the risk for
AD among smokers. The mechanisms that underlie the association between
smoking and AD are complex and could include protein misfolding, inflam-
mation, neurodegeneration and oxidative stress. Previous studies have
shown that administration of some of the cigarette components (e.g nicotin)
alter Ab aggregation in vitro and in vivo, providing a possible link. However,
extrapolation of these findings towards the in vivo situation is not straight
forward. The goal of this study was to analyze the effect of smoking under
more relevant conditions.Methods: PS1/APP double transgenic mice were
exposed to high (1h, 1 cigarette) or low (30 min, A½ cigarette) doses of to-
bacco smoke daily for 4 months, using a smoking chamber. Treatment
started at the age of 3 months and animals were sacrificed at 7 months
old. Amyloid load, microglial activation, reactive astroglial cells, and neuro-
degeneration were analyzed in hippocampal and cortical areas. Results:Aß
load was significantly increased in high dose treated animals compared with
non-treated and low dose age-matched animals using both 4G8 antibody and
Thioflavin S staining. A related inflammatory response was found in hippo-
campus and cortex using Iba1 and GFAP antibody against microglial and as-
troglial cells, respectively. Neuroinflammation correlated with the increase
in Aß burden. Likewise, FluoroJadeC-positive neurodegenerative processes
were substantially augmented and strongly associated around amyloid pla-
ques in high-dose treated animals compared to the other analyzed groups.
Conclusions:These findings provide direct evidence that smoking increases
typical neuropathological alterations associated to AD in vivo. The mecha-
nism of this effect remains to be studied. Our results suggest that cigarette
smoking may increase neurodegeneration, and thus may constitute an im-
portant environmental risk factor for AD.
P4-022 NEUROPATHOLOGYASSOCIATEDWITH
ADMINISTRATION OFA NONSELECTIVE BETA
SECRETASE (BACE) AND CATHEPSIN D
INHIBITOR IN MDR 1A/B KNOCKOUT MICE
Daniel Ness1, Manuel Buttini1, William Jordan2, Anna Liao1,
Jingsong Zhao1, Ming Chen1, Elizabeth Brigham1, William Wallace1,
George Tonn1, Erich Goldbach1, Patrick Rudewicz1, Gary Probst1,
Hing Sham1, 1Elan Pharmaceuticals, South San Francisco, California,
United States; 2Vet Path Services, Inc., Mason, Ohio, United States.
Background: Beta secretase (BACE) is an aspartyl protease that is impor-
tant in the processing of amyloid precursor protein (APP) to beta amyloid
(Aß). Cathepsin D (CatD) is a lysosomal aspartyl protease and is involved
in diverse biological functions. The objective of this study was to determine
potential safety liabilities of nonselective BACE/CatD inhibitors.Methods:
ELN 380842, a potent CatD (17 nM) and BACE (43 nM) inhibitor, was ad-
ministered to female Mdr1a/b knockout mice (6/group) twice daily (BID)
via subcutaneous injection as a vehicle control dose, a low dose (5 mg/kg/
dose), or a high escalating dose (5 mg/kg/dose for Days 1-2, 10 mg/kg/
dose for Days 3-4, 15 mg/kg/dose for Days 5-6, and 20 mg/kg/dose from
Day 7 onward) for 28 days. Results: One mouse given the high dose was
euthanized moribund on Day 28; all other mice survived. Mice given the
low or high dose demonstrated various clinical signs, including slight to se-
vere hypoactivity, brief seizure, aggressiveness and ataxia. Brain to plasma
(B/P) ratios were high. Plasma concentrations of ELN 380842 at 6 hours af-
ter the last low and high doses were 24 and 323 ng/mL, respectively; brain
levels were 2213 and 6855 ng/g, respectively. Cortical brain Aßx-40 was sig-
nificantly reduced (13% and 21%) at 6 hours post the last dose in the low and
high-dose groups, respectively, confirming that these BID doses were suffi-
cient to inhibit BACE. Microscopic changes occurred in the brain, spinal
cord, lung, and lymphoid tissues. Certain pathologies in ELN 380842-
treated mice appeared to recapitulate findings in CatD knockout mice; spe-
cifically the autofluorescent deposits observed in the brain and spinal cord,
which were associated with increases in neuronal necrosis. In addition, al-
pha-synuclein immunohistochemistry showed that ELN 380842 dose-de-
pendently led to abnormal accumulation of synaptic alpha-synuclein and
to the formation of abnormal, neurite-like alpha-synuclein positive struc-
tures in the brain. Conclusions: The neuropathology observed with ELN
380842 is likely attributable to CatD inhibition, suggesting that selectivity
against this enzyme in developing a BACE inhibitor is desirable. Further-
more, use of this pharmacologic challenge may have value in developing
models of synucleinopathies for Parkinson’s Disease research.
P4-023 PATHOGENESIS OF VASCULAR DEMENTIA
Innocent Nwankwo1, Daniele Tomassoni1, Francesco Amenta2,
Seyed Tayebati2, Enea Traini3, 1University of Camerino, Camerino, Italy;2Unicam, Camerino, Italy; 3University of Camerino, University of
Camerino, Italy.
Background: Vascular Dementia (VD) is a word for a group of symptoms
caused by disorders that affect the brain. It is not a specific disease. People
with dementia may not be able to think well enough to do normal activities,
such as getting dressed or eating. They may lose their ability to solve prob-
lems or control their emotions. They may become agitated . Vascular De-
mentia is mostly caused by complete blockage of blood vessels in the
brain, Brain damage caused by brain hemorrhage, blood vessel damage
from such disorders as lupus erythematosus or temporal arteritis. Most
Poster Presentations P4S706
cognitive testing showed de?cits in working and reference memory. Demen-
tia comes in different forms like, Creutzfeldt-Jakob Disease (CJD), Demen-
tia with Lewy Bodies Frontotemporal Dementia Huntington’s Disease .
Normal Pressure Hydrocephalus, Parkinson’s Disease Vascular Dementia
Wernicke-Korsakoff Syndrome. Alzheimer diseases. One would like to
know the role of extracellular and intraneuronal Aß accumulation in initiat-
ing neurotoxicity. Is Aß fibrils the principal toxic moiety in Alzheimer dis-
eases or whether small oligomeric assemblies serve as microglia- activating
and neuron injuring species. Is the apoptosis of neuron play an important
role in the pathogenetic Cascade of VD, that if inhibited will slow or prevent
brain dysfunction. Methods: Quantitative and qualitative evaluation using
Western blotting and immunohistochemistry ,immunofluorescence tech-
niques will be used to evaluate Amyloid beta accumulation in the extracel-
lular and intraneuronal pathways and will give a probable definition of the
activities in this cascade.Results: Expressions of protein markers present in
vascular dementia will enable us to charaterize the extent of Amyloid beta
accumulation in the extracellular and intraneuronal pathways. Morpholog-
ical features expressed after staining will ascertain the extent of damage
in the extracellular and intraneuronal morphology. The density of Beta Am-
yloid will probably indicate an important role of Aß in apoptosis of neurons.
Conclusions: The outcome of the evaluation of Aß density and immunohis-
tochemical studies will explain if the aggregation of Aß ,Aß fibrils, Apopto-
sis of neurons will play an important role in Vascular Dementia pathogenetic
cascade.
P4-024 HOW DOES DIABETES AFFECT PLAQUE AND
TANGLE PATHOLOGY IN ALZHEIMER’S
DISEASE?
Aleksandra Obradov1, Aleksandra Obradov1, Michael Malek-Ahmadi1,
Thomas Beach1, Lucia Sue1, Christine Belden1, Kathryn Davis1,
Marwan Sabbagh1, 1Banner Sun Health Research Institute, Sun City,
Arizona, United States.
Background: Past studies of AD pathology association with DM2 have pro-
vided conflicting results. While several studies indicate that subjects with
simultaneous occurrence of AD and DM2 have less AD pathology, others
have found no significant differences in AD pathology between the two
groups.Methods:Data on clinicallyand pathologically diagnosed Alzheim-
er’s disease (NINDS-ADRDA clinically andNIA Reagan intermediate or
high pathologically) with DM2 (n ¼ 30) and thosewithout DM2 (n ¼464) were included from the Banner Sun Health ResearchInstitute Brain
Donation Program by database search. Plaque and tangle scores fromthe
frontal, parietal, temporal, entorhinal and hippocampal regions werecom-
pared between the groups. In addition, summary scores from all regions
werealso compared. Mann-Whitney U test was used to compare differences
between DM2+and DM2- cases. Logistic regression wasthen used to
determine the association between total plaque and tangle countswith
DM2 status. Results: DM2+ cases had lower neurofibrillary tangle (NFT)
scores in the frontal lobe (p ¼ 0.04_ and parietal lobe p ¼ 0.07) as well
as decreased plaque scores in the CA1 hippocampal area (p ¼ 0.06). There
was no significant difference in the summary total plaque and tangle scores,
without adjustment for ApoE e 4 status. After accounting for the effect of
ApoE e 4 status, no association was found for the sum of plaque [OR
0.89 (0.64, 1.25), p ¼ .52] or sum of tangle [OR 1.09 (0.94, 1.26) p ¼.28] counts and DM2 status. Conclusions: In this clinical-pathological
case series, contrary to our hypothesis, we did not find increased plaque
and tangle histopathology in AD subjects. Instead, there was a weak trend
suggesting that AD subjects with DM2 have decreased NFT pathology in
the frontal and parietal lobes, and decreased plaque pathology in the hippo-
campus. Other data and literature reports indicate that weight loss during the
course of dementia may ameliorate many obesity-associated medical
conditions, including DM2. Further studies should examine whether DM2
in midlife is associated with increased risk and severity of neuropathologi-
cally-confirmed AD and whether DM2 prevalence and severity in AD
subjects decreases with disease duration.
P4-025 PATHOLOGICAL CORRELATES OF WHITE
MATTER HYPERINTENSITIES ON MAGNETIC
RESONANCE IMAGING
YongSoo Shim1, John Morris2, Nigel Cairns3, Tammie Benzinger2,
Chengjie Xiong4, 1The Catholic University of Korea, Bucheon, South
Korea; 2Washington University in St Louis, St Louis, Missouri, United
States; 3Washington University in St Louis, Saint Louis, Missouri, United
States; 4Washington University School of Medicine in St Louis, St. Louis,
Missouri, United States.
Background: White matter hyperintensities (WMHs) are commonly ob-
served on magnetic resonance imaging (MRI) of the brain in elderly per-
sons. We investigated the histopathological correlates of WMHs in
Alzheimer’s disease (AD) patients, controls and persons with well defined
advanced risk factors for cerebrovascular disease. Methods: From Decem-
ber 1995 to November 2000 we enrolled a total of 165 participants in the
longitudinal study of CCCVD (Cognitive Change in Cerebrovascular Dis-
ease). Even after the study ended, participants were followed for clinical
evaluations. Of the 60 participants with autopsy, MRIs were available for
57. Brain tissue was classified into white matter (WM), gray matter (GM),
cerebrospinal fluid, and WMH. Brain parenchymal fraction, an index of
brain atrophy, was calculated as sum of WM and GM volumes divided by
the total intracranial cavity volume. Neuropathological examination was
performed using the Braak and Braak neurofibrillary tangle stage and the
neuropathological criteria of the Consortium to Establish a Registry for Alz-
heimer’s Disease (CERAD). Large (atherosclerosis) and small vessel dis-
ease (arteriolosclerosis and cerebral amyloid angiopathy) were each rated.
In addition, we studied areas of tissue corresponding to WMH regions in
14 subjects. Microscopic features were added as follows: demyelination
of the deep and periventricular WM, atrophy of the ventricular ependyma,
and thickening of the blood vessels in the WM. Correlations between
MRI data and pathological findings across the entire sample were per-
formed.Results: Therewas an inverse correlation betweenWMHs and neu-
rofibrillary tangle scores (r ¼ �0.341, p ¼ 0.014). WMHs were also
decreased as neuritic and diffuse plaques (r ¼ 0.344, p ¼ 0.014 and r ¼0.280, p ¼ 0.047, respectively) get severe. Periventricular hyperintensities
correlated with breakdown of ventricular lining (r ¼ 0.559, p ¼ 0.038)
and deep white matter hyperintensities correlated with deep WM demyelin-
ation (r¼ 0.845, p¼ 0.034). Conclusions:WMHs in AD and controls con-
sist of areas of loss of myelinated axons and breakdown of the ventricular
lining, which result in a potential increase of water content. These changes
are sometimes referred to as the consequences of “small vessel disease.” We
could not find any direct association of WMHs with the arterial changes.
The pathophysiology of these lesions in the context of aging and AD
requires further scrutiny.
P4-026 EVALUATION OF RETINOBLASTOMA PROTEIN
EXPRESSION IN ASYMPTOMATIC AND
SYMPTOMATIC ALZHEIMER’S DISEASE AND
NORMAL ELDERLY SUBJECTS
Aderbal Silva1, Lea Grinberg2, Jose Farfel3, Renata Ferretti4,
Rafael Rocha1, Maria Begnami1, Helena Brentani5, 1ACCamargoHospital,
S~ao Paulo, Brazil; 2Memory and Aging Center, University of California, San
Francisco, USA, San Francisco, California, United States; 3University of
Sao Paulo, S~ao Paulo, Brazil; 4University of S~ao Paulo Medical School, S~ao
Paulo, Brazil; 5University of Sao Paulo, Sao Paulo, Brazil.
Background: The re-expression of many cell cycle-related proteins and
inappropriate cell cycle control in specific vulnerable neuronal popula-
tions in Alzheimer’s disease (AD) is emerging as an important compo-
nent in the pathogenesis leading to AD. Recent studies strongly support
the notion that the dysregulation of cell cycle in neurons ultimately
causes cell death. A very important part in the abortive cell cycle re-en-
try is played by the retinoblastoma protein (Rb) and it might be of par-
ticular interest because its activity is involved in neuronal cell death.
Methods: Using tissue specimens from postmortem human brains