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 Sangram S. Sisodia, Ph.D.
Thomas Reynolds Sr. Family Professor of Neurosciences
Director, Center for Molecular Neurobiology
Department of Neurobiology
Committee on Neurobiology
Department of Neurobiology
The University of Chicago
947 E. 58th St., MC0926
Chicago,
IL 60637
Email: ssisodia@drugs.bsd.uchicago.edu
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Research
Description
Alzheimer's disease (AD) is the most common
cause of senile dementia. 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 the 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). Over the past two decades, 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. Our approach has been to
develop cell biological strategies together with transgenic and gene
targeted mouse models to clarify these issues.
Some Selected Papers
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.
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.
Buxbaum JD, Thinakaran G, Koliatsos V,
O'Callahan J, Slunt HH, Price DL and Sisodia SS: Alzheimer amyloid
protein precursor in the rat hippocampus: transport and processing
through the perforant path. J. Neurosci. 18:9629-9637,
1998.
Orly Lazarov, Michael Lee, Daniel A.
Peterson and Sangram S. Sisodia (2002). Evidence that Synaptically
Released A b Accumulates as Extracellular Deposits in the Hippocampus
of Transgenic Mice. J. Neurosci, 15:9785-93
Kamenetz F, Tomita T, Seabrook G, Borchelt
D, Iwatsubo T, Sisodia SS and Malinow R. (2003) “APP Processing and
Synaptic Function” Neuron, 37, 925-937.
Orly Lazarov, John Robinson, Ya-Ping Tang,
Ilana S. Hairston, Zeljka Korade-Mirnics, Virginia M.-Y. Lee, Lou B.
Hersh, Robert M. Sapolsky, Karoly Mirnics and Sangram S. Sisodia (2005)
“Environmental Enrichment Reduces A b Levels and Amyloid Deposition in
Transgenic Mice” Cell, 120, 701-713
Kim S-H and Sisodia SS (2005) "Evidence that
the "NF" motif in transmembrane domain 4 of PS1 is critical for binding
with PEN-2" J. Biol. Chem. , in press
Lazarov O, Peterson LD, Peterson DA and
Sisodia SS (2005) Expression of an FAD-linked PS1 Variant Enhances
Perforant Pathway Lesion-induced Neuronal Loss in the Entorhinal Cortex
J. Neuroscience, in press
Choi S, Veeraraghavalu K, Lazarov O, Marler S, Ransohoff
R, Ramirez J, Sisodia S: Non-cell-autonomous effects of presenilin1
variants
on enrichment-mediated hippocampal progenitor cell proliferation and
differentiation. Neuron 59: 568-580,
2008.
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