Ph.D., University of Georgia
947 E 58th St MC0926
Chicago, Illinois 60637
947 E 58th St MC0926
Chicago, Illinois 60637
Sangram Sisodia, Ph.D.
Thomas Reynolds Sr. Family Professor of Neurosciences
Director, Center for Molecular Neurobiology
- Cellular & Molecular
- Neurobiology of Disease
Alzheimer’s disease (AD), a prevalent, adult-onset, neurodegenerative disease, is clinically characterized by progressive impairments in cognition and memory. These clinical features are accompanied by characteristic histological changes in the brain, including neuronal loss, extracellular deposition of fibrillogenic Ab peptides in senile plaques and intracellular neurofibrillary tangles. The principal risk factors for AD are age and inheritance of mutant genes, or polymorphic alleles that predispose individuals to disease.
Over the past 20 years, my laboratory has focused on examining the cellular and molecular biology of the b-amyloid precursor protein (APP), or presenilins (PS1 and PS2), molecules that are mutated in pedigrees with autosomal dominant, familial forms of Alzheimer's disease (FAD). The function(s) of APP in the central nervous system (CNS) are still not fully understood, but we have demonstrated that APP is subject to rapid anterograde axonal transport and subject to proteolytic processing at, or near, terminal fields. In collaboration with Robert Malinow at UCSD, we have also shown that synaptic activity modulates APP processing and Ab production, and that both axonal and dendritic release of these peptides alter spine dynamics and glutamatergic neurotransmission. Our current efforts are focused on clarifying the dynamics and regulation of APP trafficking and processing cultured neurons and hippocampal slices using recombinant lentiviral-driven APP-GFP chimeras and live cell imaging approaches. In order to assess the normal function of PS, we have used gene targeting strategies; PS1-deficient animals die in late embryogenesis due to defective Notch signaling that is in large part, the result of failed intramembranous, “g-secretase” processing of a membrane-bound Notch substrates. This “g-secretase” activity is also responsible for liberating Ab peptides from membrane-bound APP derivatives. We, and others, have provided genetic and biochemical evidence has revealed that PS associates with nicastrin (NCT), APH-1 and PEN-2 in high molecular weight complexes, and our current efforts are aimed at understanding the temporal assembly of these membrane proteins, the nature of subunit interactions and the enzymatic mechanism(s) by which the complex promotes “g-secretase” processing of Notch, APP and other type 1 membrane proteins. In parallel, we have an ongoing collaboration with Iban Ubarratexna at Mt. Sinai to determine the structure of the “g-secretase” complex using single particle- and cryo-EM approaches. Finally, and in collaboration with Tony Kossiakof and Shohei Koide at the University of Chicago, we are determining the crystal structure of NCT, the polypeptide that binds and delivers transmembrane substrates to the complex.
A significant effort of our laboratory has been to develop and characterize transgenic animals that express FAD-linked variants of PS1 and APP to clarify the underlying biochemical and pathophysiological alterations that cause AD. We have exploited these animals, as well as animals in which we have conditionally inactivated PS, to clarify issues relevant to axonal trafficking of membrane proteins, neurodegeneration, neuronal vulnerability, gene expression and APP/Ab metabolism. A significant effort in our laboratory is focused on understanding the cell non-autonomous effects of FAD-linked mutant PS1 expression on hippocampal neurogenesis. Our future studies will focus heavily on the mechanisms that are responsible for the observed effects using temporal and system-specific conditional gene inactivation approaches. Extending our demonstration that enriched environments and exercise modulates Ab metabolism and deposition in vivo, our ongoing efforts are focused on the role of polypeptides encoded by genes that are selectively regulated in these settings.
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. The value of animal models that recapitulate some features of the human disease have, and will be of enormous value for addressing issues relevant to the selective vulnerability of specific CNS systems, the pathophysiological sequelae and ultimately, and will provide opportunities to explore mechanism-based therapeutic strategies.
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
Sisodia SS, Koo EH, Hoffman PN, Perry G and Price DL: Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J. Neurosci. 13: 3136 3142, 1993.
Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitski T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins N, Copeland N, Price DL and Sisodia SS: Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17: 181 190, 1996.
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.
Lazarov, O. Lee, M. Peterson, DA and Sisodia SS.. Evidence that Synaptically Released Abeta Accumulates as Extracellular Deposits in the Hippocampus of Transgenic Mice. J. Neurosci, 15:9785-93, 2002.
Lazarov O, Robinson J, Tang Y-P, Hairston IP, Korade-Mirnics Z, Lee V M-Y, Hersh LB, Sapolsky RB, Mirnics K and Sisodia SS. Environmental Enrichment Reduces Abeta Levels and Amyloid Deposition in Transgenic Mice. Cell, 120, 701-713, 2005
Lazarov O, Pigino G, Morfini GA, Gadadhar A, Chen X, Robinson J, Ho H,Brady ST, Sisodia SS (2007) Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing FAD-Linked mutant PS1. J. Neuroscience, 27: 7011-7020.
Choi S, Leight SN, Lee V M-Y, Li T, Wong PC, Johnson JA, Saraiva MJ and Sisodia SS. Accelerated A? deposition in APPswe/PS1?E9 mice with hemizygous deletions of TTR (Transthyretin). J.Neuroscience, 27: 7006-7010 (2007).
Choi S, Veeraraghavalu K, Lazarov O, Marler S, Ransohoff RM, Ramirez JM and Sisodia SS (2008) FAD-linked human Presenilin 1 variants impair environmental enrichment-induced hippocampal neural progenitor cell proliferation and differentiation in a non-cell autonomous manner. Neuron, 59, 568-580