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.

Public Health Relevance

It is now well established that the numbers of dividing stem cells destined to generate new neurons in the hippocampus, a region critical for memory formation, decline during human aging and in Alzheimer's disease (AD), the most prevalent dementing disorder of the elderly. We have shown mutant presenilin 1 (PS1) genes that cause familial AD impairs the production of new neurons in the hippocampus of mouse models as a result of altering the biology of non-neuronal cells in the environment. Our studies to Identify the cells and mechanisms that impact on stem cell biology in the hippocampus may provide opportunities toward the development of regenerative therapeutics for AD and hence, are highly relevant to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG040185-02
Application #
8321961
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Wise, Bradley C
Project Start
2011-09-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$391,536
Indirect Cost
$137,697
Name
University of Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Veeraraghavalu, Karthikeyan; Zhang, Can; Zhang, Xiaoqiong et al. (2014) Age-dependent, non-cell-autonomous deposition of amyloid from synthesis of β-amyloid by cells other than excitatory neurons. J Neurosci 34:3668-73
Veeraraghavalu, Karthikeyan; Sisodia, Sangram S (2013) Mutant presenilin 1 expression in excitatory neurons impairs enrichment-mediated phenotypes of adult hippocampal progenitor cells. Proc Natl Acad Sci U S A 110:9148-53
Veeraraghavalu, Karthikeyan; Choi, Se Hoon; Zhang, Xiaoqiong et al. (2013) Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors. Mol Neurodegener 8:41
Zhang, Xulun; Garbett, Krassimira; Veeraraghavalu, Karthikeyan et al. (2012) A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2. J Neurosci 32:8633-48
Veeraraghavalu, Karthikeyan; Choi, Se Hoon; Zhang, Xiaoqiong et al. (2010) Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling. J Neurosci 30:6903-15