Sangram S. Sisodia, Ph.D.

Headshot photo

Thomas A. Reynolds Sr. Family Professor of Neurosciences, University of Chicago
Director, Center for Molecular Neurobiology

Dr. Sisodia is a leading expert on the molecular and cell biology of Alzheimer's disease pathology. He has been at the forefront of learning how the familial Alzheimer's disease (FAD) genes, including the amyloid precursor protein and the presenilins, function normally, and contribute to Alzheimer's disease pathogenesis. Most recently, Dr. Sisodia's studies have shown that in mice, exercise has a remarkable ability to protect against Alzheimer's disease pathology by favorably changing gene activity in the brain.

Funded Research

Project Description Researchers Funding
In Vitro and In Vivo Analysis of APP Variants

It is widely accepted that Abeta peptides, the principal component of senile plaques, play a causative role in the pathogenesis of Alzheimer’s disease (AD). Abeta is derived from larger beta-amyloid precursor proteins (APP). Early-onset, familial AD (FAD) is caused by inheritance of mutations in genes encoding APP or presenilin (PS1 or PS2) variants. Mutations in APP lead to the production of elevated levels of Abeta or the ratio of Abeta42/40 peptides. Importantly, all of the known APP mutations reside proximal to, or within, the Abeta peptide sequence.

Mechanisms By Which the Gut Microbiome Influences Amyloid Deposition and Neuroinflammation in Mouse Models of Alzheimer’s Disease

In our earlier proposal, we tested the hypothesis that the composition of the intestinal microbiome might play a key role in modulating neuroinflammation that, in turn, influences Abeta deposition. We have demonstrated that long-term treatment with an antibiotic (ABX) cocktail does not alter total bacterial abundance in either the cecum or feces, but rather, induces a distinct perturbation in gut microbial diversity. The alterations in bacterial diversity are paralleled by selective changes in the levels of several circulating cytokines/chemokines in the blood sera.

The Role of Microbial Immune Responses in Alzheimer’s Disease

Animal models of Alzheimer’s disease (AD) recapitulate the severe amyloidosis and neuroinflammation that is evident in the human disease. While it long has been assumed that inflammation associated with amyloid deposition reflects the activation of astrocytes and microglia into proinflammatory M1 states in response to injury, there is a paucity of information regarding the potential role of peripheral tissues and, more importantly, the microbiota in regulating innate immunity that in turn leads to CNS dysfunction.

Investigations of the Mechanism of Action of TagretinR/Bexarotene on Amyloid Clearance in Transgenic Mouse Models

Recent studies from the laboratory of Dr. Gary Landreth (Cramer P. et. al (2012) Science 335) have demonstrated that Bexarotene (Targretin), a highly selective, blood-brain barrier-permeant, FDA-approved, RXR agonist for the treatment of cutaneous T-cell lymphoma, can rapidly reduce amyloid plaque burden and rescue behavioral deficits in transgenic mouse models of AD. The proposed mechanism of action is via transcriptional activation of PPARγ:RXR- and LXR:RXR-regulated genes, including ApoE, ABCA1 and ABCG1 expression, that facilitates Aβ clearance and promotes microglial phagocytosis.

Modulation of Abeta Deposition by Cell-Specific Mechanisms

The goal of this project is to determine which types of cells and factors in the brain influence excess Abeta deposition in Alzheimer’s patients, using animal models of the disease.

2010 to 2011

Oligomer Collaborative Projects

A collaboration of members of the Research Consortium, a member of the Cure Alzheimer’s Fund Science Advisory Board and non-Cure Alzheimer’s Fund-affiliated researchers hypothesizes that an abnormal increase in levels of synaptic Abeta and, particularly, Abeta oligomers may lead to synaptic dysfunction, cognitive decline and eventually dementia. This highly innovative collaborative project will address how Abeta oligomers are formed and which types detrimentally impact synaptic dysfunction and neuronal survival in the brain.

2006 to 2008

Molecular Mechanism Underlying Hippocampal Neurogenisis by Familial AD-linked Presenilin-1 Variants

The specific hypothesis behind the proposed research is that presenilin 1 regulates cell fate determination of adult neural progenitor cells by interfering with instructive intercellular signals prevailing within the neural progenitor cell niche, and that expression of the familial AD-linked presenilin 1adversely affects this process.


Selected Publications

These published papers resulted from Cure Alzheimer’s Fund support.
Xulun Zhang, Eric Sullivan, Maggie Scimeca, Xianzhong Wu, Yue-ming Li and Sangram S. Sisodia, Evidence That the "Lid" Domain of Nicastrin Is Not Essential for Regulating γ-Secretase Activity, Journal of Biological Chemistry, 291(13), 25 Mar 2016, 6748-53
Karthikeyan Veeraraghavalu, Can Zhang, Xiaoqiong Zhang, Rudolph E. Tanzi, and Sangram S. Sisodia, Age-Dependent, Non-Cell-Autonomous Deposition of Amyloid from Synthesis of β-Amyloid by Cells Other Than Excitatory Neurons, J Neurosci, 34(10), 5 March 2014, 3668-3673
Xulun Zhang1, Krassimira Garbett2, Karthikeyan Veeraraghavalu, Brian Wilburn, Reid Gilmore, Karoly Mirnics, and Sangram S. Sisodia, A Role for Presenilins in Autophagy Revisited: Normal Acidification of Lysosomes in Cells Lacking PSEN1 and PSEN2, The Journal of Neuroscience, 32(25), June 20, 2012, 8633-8648
Prinz M, Priller J, Sisodia SS, Ransohoff RM, Heterogeneity of CNS myeloid cells and their roles in neurodegeneration, Nat Neurosci., 14(10), 2011 Sept 27, 1227-35
Kwangwook Ahn, Christopher C. Shelton, Yuan Tian, Xulun Zhang, M. Lane Gilchrist, Sangram S. Sisodia, and Yue-Ming Li, Activation and Intrinsic γ-Secretase Activity of Presenilin 1, Proc. Natl. Acad. Sci USA, 50, Oct 15, 2010, 21435–21440
Wei W, Nguyen L, Kessels HW, Hagiwara H, Sisodia S, Malinow R, Amyloid beta from axons and dendrites reduces local spine number and plasticity, Nature Neuroscience, 13(2), Feb 2010, 190-196
Choi SH, Li Y, Parada LF, Sisodia SS, Regulation of hippocampal progenitor cell survival, proliferation and dendritic development by BDNF, Mol Neurodegener, 4, Dec 21, 2009, 52
Meier M, Kennedy-Darling J, Choi SH, Norstrom EM, Sisodia SS, Ismagilov RF, Plug-Based Microfluidics with Defined Surface Chemistry to Miniaturize and Control Aggregation of Amyloidogenic Peptides, Angewandte Chemi International Edition, Volume 48 Issue 8, February 9, 2009, 1487–1489
Choi SH, Veeraraghavalu K, Lazarov O, Marler S, Ransohoff RM, Ramirez JM, Sisodia SS, Non-Cell-Autonomous Effects of Presenilin 1 Variants on Enrichment-Mediated Hippocampal Progenitor Cell Proliferation and Differentiation, Neuron, Volume 59, Issue 4, August 28, 2008, 568-580
Choi SH, Leight SN, Lee VM-Y, Li T, Wong PC, Johson JA, Saraiva MJ, Sisodia SS, Accelerated Aβ Deposition in APPswe/PS1∆E9 Mice with Hemizygous Deletions of TTR (Transthyretin), J Neurosci, (26), 2007, 7006-7010