The Role of PICALM in Regulating Neurogenesis in Alzheimer's Disease

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.

Grant Number: 5F30AG086007-02
NIH Institute/Center: NIH
Principal Investigator: Luis Aponte-Cofresi