P1‐034: UPREGULATION OF ENDOTHELIAL PICALM EXPRESSION USING AN FDA‐APPROVED DRUG REDUCES AMYLOID‐β LOAD IN THE MURINE BRAIN

PICALM, phosphatidylinositol binding clathrin assembly protein, is a known genetic risk factor in Alzheimer's disease (AD). PICALM is highly expressed in brain endothelial cells, and involved in clathrin-mediated endocytosis, trafficking, and clearance of amyloid-β (Aβ) from the brain across the blood-brain barrier (BBB). However, PICALM brain endothelial levels are reduced in AD. We have previously shown that PICALM endothelial reduction leads to reduced Aβ clearance from brain and exacerbation of Aβ pathology. Thus, therapeutic strategies to upregulate PICALM expression in the vasculature could represent a novel therapeutic target for AD treatment. 2,007 FDA-approved drugs were screened in vitro for upregulation of PICALM. We treated 5XFAD mouse model of AD carrying a single copy of the Picalm gene (Picalm+/-; 5XFAD) to mimic features of AD, or 5XFAD mice with a genetic deletion of Picalm from endothelium with the top hit drug, T-65, for two months beginning at 3 months of age. Vascular PICALM levels, brain Aβ load, and behavior were evaluated after treatment. Treatment of Picalm+/-; 5XFAD mice with T-65 increased endothelial PICALM levels 2-fold, reduced brain Aβ load in cortex and hippocampus by 40-60%, and improved behavioral performance compared to vehicle treated littermates. T-65 treatment did not alter APP processing or Aβ degrading enzymes, as shown by comparable APP, BACE1, soluble APP-β, Neprilysin, and IDE levels in drug- and vehicle-treated groups. In 5XFAD mice with endothelial-specific Picalm deletion, no reduction in brain Aβ load was observed after treatment. These data indicate that PICALM upregulation in the endothelium with T-65 treatment enhances Aβ clearance leading to reduced amyloid load and improved cognitive function in mice. T-65-mediated increase in PICALM expression may provide an important new therapeutic avenue for AD.