Presenilin Variants in the Modulation of Hippocampal Neurogenesis

Summary

Principal Investigator: Sangram S Sisodia
Abstract: DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by impairments in memory and cognition, neuronal loss and deposition of beta-amyloid (Abeta) peptides that are derived from larger amyloid precursor proteins (APP). Inheritance of mutated PSEN1 and PSEN2 genes, encoding presenilin 1 and presenilin 2 (PS1 and PS2) variants, respectively, cause early-onset, autosomal dominant forms of familial AD (FAD), an aggressive form of disease that affects patients in the second to fifth decades of life (Price and Sisodia, 1998). We have demonstrated that expression of human FAD-linked PS1 variants in all CNS cell types in transgenic mice impairs environmental enrichment (EE)-induced division (termed proliferation) and production of new neurons (termed neurogenesis) of precursor cells (termed NPCs) in the hippocampus (Choi et al., 2008), and the experiments proposed in this application are designed to clarify the molecular and cellular mechanism(s) by which these mutant PS1 variants alters the homeostasis of hippocampal NPCs. Because the hippocampal NPCs provide a cellular reservoir for replacement of granule cells during normal aging, we suggest that in AD, mechanisms responsible for NPC division and neuronal differentiation are impaired and hence cannot fully compensate for the severe neuronal loss in disease. Indeed, recent studies have revealed a marked reduction in the numbers of NPC and their derivatives in brains of aged humans and patients with AD. As the hippocampus plays a central role in memory formation, understanding the physiological and molecular underpinnings of mutant PS1 on NPC proliferation and neurogenesis is critical. To this end, we have shown that proliferation and neurogenesis of hippocampal NPCs are controlled, at least in part, by microglial cells in the hippocampal niche by non-cell autonomous mechanisms. We now propose three Aims in which we will employ biochemical and genetic strategies to elucidate the cellular and molecular mechanisms underlying the effects of FAD-linked PS1 on proliferation and neuronal differentiation of adult hippocampal progenitors.
Funding Period: 2011-09-01 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. pmc Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation
    Se Hoon Choi
    Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA
    Neuron 59:568-80. 2008
  2. pmc Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling
    Karthikeyan Veeraraghavalu
    Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA
    J Neurosci 30:6903-15. 2010

Research Grants

  1. ALZHEIMER DISEASE RESEARCH CENTER
    HELENA CHANG CHUI; Fiscal Year: 2013
  2. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
  3. ALZHEIMERS DISEASE RESEARCH CENTER
    John Morris; Fiscal Year: 2013
  4. Sleep/Wake Fragmentation with Age: Molecular Mechanisms
    ALLAN IAN PACK; Fiscal Year: 2013
  5. Massachusetts Alzheimer's Disease Research Center
    Bradley T Hyman; Fiscal Year: 2013
  6. The Role of CX3CR1 Signaling in Alzheimer's Disease Pathogenesis
    Sungho Lee; Fiscal Year: 2013
  7. Presenilin dysfunction in the brain
    Raymond J Kelleher; Fiscal Year: 2013
  8. Wisconsin Alzheimer's Disease Research Center
    Sanjay Asthana; Fiscal Year: 2013
  9. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
  10. Alzheimer's Disease Research Center at Columbia University
    Scott A Small; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation
    Se Hoon Choi
    Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA
    Neuron 59:568-80. 2008
    ....
  2. pmc Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling
    Karthikeyan Veeraraghavalu
    Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA
    J Neurosci 30:6903-15. 2010
    ..Hence, we argue that a partial reduction in PS-dependent gamma-secretase processing of the Notch, at least in part, accounts for the impairments observed in SVZ NPCs expressing the FAD-linked PS1DeltaE9 variant...

Research Grants30

  1. ALZHEIMER DISEASE RESEARCH CENTER
    HELENA CHANG CHUI; Fiscal Year: 2013
    ..abstract_text> ..
  2. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  3. ALZHEIMERS DISEASE RESEARCH CENTER
    John Morris; Fiscal Year: 2013
    ..Changing tau protein levels and tau protein isoforms in mouse models of dementia;(Timothy Miller) 3. APOE metabolism in AD and controls;(Randall Bateman). ..
  4. Sleep/Wake Fragmentation with Age: Molecular Mechanisms
    ALLAN IAN PACK; Fiscal Year: 2013
    ..These three projects are supported by three cores;a) Administrative Core;b) Mouse Behavioral Core;and c) Biostatistics and Bioinformatics Core. ..
  5. Massachusetts Alzheimer's Disease Research Center
    Bradley T Hyman; Fiscal Year: 2013
    ..Going forward, the MADRC will continue to expand its clinical and neuropathological resources, its innovative training and scientific programs directed toward AD research. ..
  6. The Role of CX3CR1 Signaling in Alzheimer's Disease Pathogenesis
    Sungho Lee; Fiscal Year: 2013
    ..In Specific Aim 3, Cx3cr1-deficient microglia will be examined for their capacity to phagocytose A-beta and migrate to stereotactically injected A-beta. ..
  7. Presenilin dysfunction in the brain
    Raymond J Kelleher; Fiscal Year: 2013
    ....
  8. Wisconsin Alzheimer's Disease Research Center
    Sanjay Asthana; Fiscal Year: 2013
    ..abstract_text> ..
  9. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  10. Alzheimer's Disease Research Center at Columbia University
    Scott A Small; Fiscal Year: 2013
    ..HIPAA compliant data organization and statistical consulting services are provided under the ADRC to the research community at Columbia and external to it. ..
  11. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
    ..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
  12. Stem Cells for Brain Repair
    DANIEL ALAN PETERSON; Fiscal Year: 2013
    ..This study will include both young and aged animals to address this important, clinically relevant factor. ..
  13. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  14. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  15. GSK-3 is a Master Regulator of Neural Progenitor Self-Renewal
    William D Snider; Fiscal Year: 2013
    ..Our results may also suggest new ways to expand neural stem cells in the setting of neural transplantation ..
  16. The amyloid cascade in a novel mouse model of Alzheimer's disease
    Carol Anne Colton; Fiscal Year: 2013
    ..The third aim will examine a likely mechanism of NO's action, the regulation of caspase activity. ..
  17. Beta-Amyloid Immunization in a Canine Model of Aging
    Elizabeth Head; Fiscal Year: 2013
    ..abstract_text> ..
  18. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  19. APP/AB/Tau biochemistry in transgenic mice, familial and sporadic AD
    Alex E Roher; Fiscal Year: 2013
    ..A more complete understanding of AD molecular phenotypes and their clinical responses will aid in the discovery and application of efficacious treatments that will prevent AD or enhance the quality of life of AD patients. ..
  20. Alzheimer's Disease Research Center
    Thomas J Montine; Fiscal Year: 2013
    ..Montine;Project 2: Therapeutic Effects of Intra-Nasal Insulin Detemir, Dr. Suzanne Craft;Project 3: Modulation of A peptide accumulation and neuron damage in vivo with adult bone marrow transplants, Dr. C. Dirk Keene. ..
  21. Modifiers of Beta-Amyloid Metabolism and Deposition
    Bruce T Lamb; Fiscal Year: 2013
    ..2) Identify and characterize genetic loci that regulate A[unreadable] deposition. 3) Characterize genetic loci responsible for diet-induced alterations in A[unreadable] metabolism and deposition. ..