Alzheimer’s disease

Enrichment-induced neurogenesis in adult mouse hippocampus: modulation by FAD-linked PS1 variants
2007 Seed Grant
Sangram Sisodia, Ph.D.
The University of Chicago

Alzheimer disease (AD) is a neurological disorder characterized by slow, progressive memory loss due to a gradual loss of brain cells. AD significantly affects cognitive (thought) capabilities and, eventually, affected individuals become incapacitated. Alzheimer-related issues can cause emotional and financial upheaval for both the individuals with the disease and their families. AD is the most common form of dementia (loss of intellectual function) and, according to the National Institutes of Health, it is the fourth leading cause of death in elderly Americans. Up to 25% of diagnosed cases are thought to be part of a familial-based inheritance pattern. A low percentage of these cases results from inheritance of mutations in Presenilinl gene, which pre-disposes them for to disease symptoms as early as at the age of -30. years. Understanding the normal functions of Presenilinl and the mechanisms by which mutated versions of this protein causes AD remains elusive, and is an area of active research for the past decade. One of the fundamental issues, which is under explored in this regard, is the question pertaining to the cell type that is most vulnerable to mutant Presenilin proteins. Based on the preliminary results presented here, Dr. Sisodia and his lab propose to elucidate how non-neuronal cell types harboring Presenilin mutations could impair birth and survival of healthy neurons in the adult brain. The outcome of this study could bring new insights into the target cell types and pathways affected in early-onset forms of AD.

It is now well established that birth of new neurons take place throughout adulthood in certain specific areas like hippocampus, a region in the brain, involved in learning/memory and is adversely affected in AD patients. Adult neurogenesis is primarily driven by committed neural progenitor cells that exist in low abundance within hippocampus. These progenitors provide a cellular reservoir for replacement of cells lost during normal turnover or pathological situations prevailing in neurodegenerative disorders. Expansion and differentiation of neural progenitors are tightly regulated by factors encountered in the surrounding neural progenitor niche. Of late, it has become evident that Presenilinl may influence growth and differentiation properties of neural progenitors. Given that mutant forms of Presenilinl have a great impact in initiation and progression of early onset forms of AD, it is of importance to examine whether they adversely affect neurogenesis in the adult brain. Dr. Sisoda and his lab propose to test the effect of familial AD-linked Presenilinl mutants in mouse models and in cultured neural progenitors. They will undertake experiments to identify whether non-neural progenitor cell types like microglia, are vulnerable to mutant Presenilinl. This study will provide a better understanding on the role of Presenilins in maintaining a healthy environment within neural stem cell niche.

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