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, OPeterson 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

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