| Senile dementia is a syndrome characterized by impaired
memory and
cognitive capacities that occurs in the elderly. Alzheimer's
disease
(AD) is the most common cause of senile dementia and affects 7% of
individuals
over 65 years of age and 40% of individuals over 80 years of age.
Because life expectancies have increased, the old, a population at risk
for AD, is the fastest growing segment of our society. AD
selectively
affects neurons in neocortex, hippocampus, basal forebrain, and several
brainstem monoaminergic nuclei. Affected brain regions contain
many
senile plaques comprised of neurites displayed around extracellular
deposits
of bamyloid, a 4 kDa peptide derived from
larger
amyloid precursor proteins (APP). Diseased nerve cells often
exhibit
alterations in the neuronal cytoskeleton, and these cellular
abnormalities
in specific neuronal circuits have profound clinical consequences and
represents
the biological substrates of the dementia.
Over the past ten years, molecular geneticists have
identified genes
that are mutated in pedigrees with early-onset, autosomal dominant
forms
of AD (FAD). These genes encode presenilin 1 (PS1), presenilin 2 (PS2),
and APP. Research in my laboratory has focused on understanding the
normal
biology of APP, PS1 and PS2, and the molecular and cellular mechanisms
by which mutated versions of these interesting proteins cause AD.
We have employed a variety of cell biological, transgenic and gene
targeting
approaches to clarify these issues. For example, we used gene targeting
strategies to functionally inactivate the mouse PS1 gene; these animals
die in late embryogenesis due to defective Notch signaling. In
addition,
we have generated transgenic mice expressing FAD-linked PS1 and human
APP
that exhibit fairly selective deposition of b amyloid
in hippocampus and cortex. These animals offer tremendous opportunities
to begin to evaluate the evolution and character of amyloid deposition
and associated cellular abnormalities, the physiological responses to
deposition
and potentially, behavioral manifestations.
In summary, my research program is designed to integrate
genetic, neurobiologic,
molecular and cellular information to clarify the normal biology of APP
and PS and the mechanisms by which mutant genes cause AD. Our
development
of animal models that recapitulate some features of the human disease
will
be useful for addressing issues relevent to the selective vulnerability
of specific CNS systems, the pathophysiological sequelae and provide
opportunities
to test agents which block these processes.
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| Sisodia SS, Koo EH, Beyreuther K, Unterbeck A and Price
DL: Evidence
that ß-amyloid protein in Alzheimer's disease is not derived by
normal
processing. Science 248: 492-495, 1990.
Sisodia SS: ß-amyloid precursor protein
cleavage by a membrane-bound
protease. Proc. Natl. Acad. Sci. USA 89: 6075-6079, 1992.
Thinakaran G, Kitt CA, Roskams AJI, Slunt HH, Masliah E,
von Koch C,
Ginsberg SD, Ronnett GV, Reed RR, Price DL and Sisodia SS:
Distribution
of an APP homolog, APLP2, in the mouse olfactory system; a potential
role
for APLP2 in axogenesis. J. Neurosci. 15: 6314-6326, 1995.
Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji
DJS, Trumbauer
ME, Chen HY, Price DL, Van der Ploeg LHT and Sisodia SS:
Presenilin
1 is required for Notch1 and Dll1 expression in the paraxial mesoderm.
Nature 387: 288-292, 1997.
Borchelt DR, Ratovitski T, Van Lare J, Lee MK, Gonzales
VB, Jenkins
NA, Copeland NG, Price DL and Sisodia SS: Accelerated amyloid
deposition
in the brains of transgenic mice co-expressing mutant presenilin 1 and
amyloid precursor proteins. Neuron 19: 939-945, 1997.
Naruse S, Thinakaran G, Luo J-J, Kusiak JW, Tomita T,
Iwatsubo T, Qian
X, Ginty DD, Price DL, Borchelt DR, Wong PC and Sisodia SS.
Effects
of PS1 deficiency on membrane protein trafficking in Neurons.
Neuron
20:603-609, 1998.
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![[ Sangram S. Sisodia ]](sSisodia.gif)