Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Ninety five percent of AD cases are sporadic late onset (LOAD) of unknown cause. Aging is the greatest risk factor of LOAD. Pathologically, AD is characterized by brain aggregates of β-amyloid (Aβ) and neurofibrillary tangles. Clinically it is characterized by progressive memory loss and cognitive deficits. Hippocampal-dependent episodic memory is the earliest deficit to be clinically detected and the most severely impaired throughout disease progression. Adult hippocampal neurogenesis (AHN) is an integral process for hippocampal memory formation that occurs in the dentate gyrus (DG). We and others have shown that AHN is impaired in AD mouse models and patients. Several genome-wide association studies (GWAS) have identified PICALM, the gene encoding for Phosphatidylinositol Binding Clathrin Assembly Protein, as a genetic risk factor for LOAD. However, how PICALM polymorphism induces pathology and memory loss is yet to be fully understood. My preliminary studies show that PICALM is expressed in neural stem and progenitor cells (NSPCs) in the mouse hippocampus, as well as in neurons derived from human induced pluripotent stem cells (iPSC), and its expression appears to be stage-specific. Further, knocking out PICALM in iPSC- derived neural progenitor cells, precursors and new neurons reduced levels of b- III-tubulin and neurofilament, suggesting that PICALM regulates neuronal maturation. Additionally, the ratio between the mature and immature form of b-Amyloid precursor protein (b-APP) was altered in PICALM KO cells throughout neurogenesis stages, suggesting that PICALM regulates b-APP metabolism. Interestingly, levels of PICALM in the hippocampus of adult mice are significantly reduced with age, while its cleavage products are increased. Thus, we hypothesize that PICALM regulates AHN and b-APP metabolism, and that altered expression of PICALM in NSPCs in LOAD impairs AHN and contributes to amyloidosis and hippocampus-dependent memory deficits. To address this hypothesis, experiments in Aim 1 will examine the role of PICALM in AHN using a conditional knockout of PICALM in AHN in mice and determine its role in AHN-dependent learning and memory. Aim 2 will elucidate the role of PICALM in impaired neurogenesis and amyloidosis in AD in iPSC- derived human forebrain neurons harboring PICALM polymorphisms and PICALM knockout. These experiments will provide new information about a novel regulator of hippocampal neurogenesis and a mechanism by which AHN is impaired in LOAD and contributes to pathology and memory loss.

Project Narrative: The cause of memory loss in Alzheimer’s disease remains largely unknown. It is essential to understand the molecular mechanisms underlying hippocampus-dependent learning and memory, the earliest and most affected by the disease. This project will determine the role of the Late onset Alzheimer’s disease – linked PICALM in adult hippocampal neurogenesis and establish PICALM as a novel contributor to hippocampus-dependent memory impairments in Alzheimer’s disease.