Sangram S. Sisodia, PhD

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 late-onset 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.



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. Finally, we have been exploring the impact of the microbiome in modulation of amyloid deposition in mouse models of AD.



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, will provide opportunities to explore mechanism-based therapeutic strategies.

Presenilin 1 in migration and morphogenesis in the central nervous system.
Louvi A, Sisodia SS, Grove EA. Presenilin 1 in migration and morphogenesis in the central nervous system. Development. 2004 Jul; 131(13):3093-105.
PMID: 15163631

Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE.
Im H, Manolopoulou M, Malito E, Shen Y, Zhao J, Neant-Fery M, Sun CY, Meredith SC, Sisodia SS, Leissring MA, Tang WJ. Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J Biol Chem. 2007 Aug 31; 282(35):25453-63.
PMID: 17613531

Familial British dementia: expression and metabolism of BRI.
Kim SH, Wang R, Gordon DJ, Bass J, Steiner DF, Thinakaran G, Lynn DG, Meredith SC, Sisodia SS. Familial British dementia: expression and metabolism of BRI. Ann N Y Acad Sci. 2000; 920:93-9.
PMID: 11193182

Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia.
Kim SH, Wang R, Gordon DJ, Bass J, Steiner DF, Lynn DG, Thinakaran G, Meredith SC, Sisodia SS. Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia. Nat Neurosci. 1999 Nov; 2(11):984-8.
PMID: 10526337

Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1?E9 murine model of Alzheimer's disease.
Minter MR, Hinterleitner R, Meisel M, Zhang C, Leone V, Zhang X, Oyler-Castrillo P, Zhang X, Musch MW, Shen X, Jabri B, Chang EB, Tanzi RE, Sisodia SS. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1?E9 murine model of Alzheimer's disease. Sci Rep. 2017 09 05; 7(1):10411.
PMID: 28874832

Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion.
Ortega-Martinez S, Palla N, Zhang X, Lipman E, Sisodia SS. Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion. J Neurosci. 2019 Aug 21; 39(34):6766-6780.
PMID: 31217332

Sex-specific effects of microbiome perturbations on cerebral Aß amyloidosis and microglia phenotypes.
Dodiya HB, Kuntz T, Shaik SM, Baufeld C, Leibowitz J, Zhang X, Gottel N, Zhang X, Butovsky O, Gilbert JA, Sisodia SS. Sex-specific effects of microbiome perturbations on cerebral Aß amyloidosis and microglia phenotypes. J Exp Med. 2019 Jul 01; 216(7):1542-1560.
PMID: 31097468

Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging.
Füger P, Hefendehl JK, Veeraraghavalu K, Wendeln AC, Schlosser C, Obermüller U, Wegenast-Braun BM, Neher JJ, Martus P, Kohsaka S, Thunemann M, Feil R, Sisodia SS, Skodras A, Jucker M. Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging. Nat Neurosci. 2017 Oct; 20(10):1371-1376.
PMID: 28846081

Cell-targetable DNA nanocapsules for spatiotemporal release of caged bioactive small molecules.
Veetil AT, Chakraborty K, Xiao K, Minter MR, Sisodia SS, Krishnan Y. Cell-targetable DNA nanocapsules for spatiotemporal release of caged bioactive small molecules. Nat Nanotechnol. 2017 12; 12(12):1183-1189.
PMID: 28825714

Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease.
Minter MR, Zhang C, Leone V, Ringus DL, Zhang X, Oyler-Castrillo P, Musch MW, Liao F, Ward JF, Holtzman DM, Chang EB, Tanzi RE, Sisodia SS. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease. Sci Rep. 2016 07 21; 6:30028.
PMID: 27443609

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