Validating a Novel Lipid Phosphatase Target in Alzheimer's Disease
Description: PUBLIC HEALTH RELEVANCE: Alzheimer's disease is characterized clinically by memory impairment and pathologically by the deposition of amyloid-2 peptide (A2) in the brains of AD patients. Evidence is accumulating which supports the hypothesis that A2 may be a factor in early neuronal dysfunction associated with AD. Specifically, levels of A2 correlate with disease progression in animal models of AD. In the brain, A2 interferes with normal neuronal function by mechanisms that are not yet fully understood. We have recently published data indicating that a specific lipid, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], which regulates key aspects of neural function, is altered after treatment of neurons with A2. Additionally, mice with low levels of a specific lipid phosphatase, synaptojanin 1 (Synj1), responsible for metabolizing PI(4,5)P2, are resistant to A2-induced neuronal dysfunction. We propose to further investigate the role Synj1 in A2-induced neuronal dysfunction by using mutants of Synj1 to probe its function in neurons lacking endogenous Synj1. Additionally, we propose to cross a mouse model of AD with mice lacking one copy of Synj1. Since this genotype was protective in vitro, we expect these mice to have ameliorated AD-associated behavioral deficits in learning and memory tasks. Completion of these studies will determine if Synj1 can be a valid target for future AD therapeutic strategies.
Funding type: research
Funder scheme: R01
Start date: 2011-01-15
End date: 2015-12-31
Investigator: TAE-WAN KIM
Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 9
Funder award ID: R01NS074536
OpenAlex ID: G251617455