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P1‐036: NEURON‐TARGETED CAVEOLIN‐1 GENE THERAPY PRESERVES COGNITIVE FUNCTION AND SYNAPTIC PLASTICITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE (AD)
Author(s) -
Wang Shanshan,
Leem Joseph,
Fan Mckenzie,
Kleschevnikova Natalia,
Head Brian
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.061
Subject(s) - synaptophysin , synaptic plasticity , hippocampus , synapsin i , hippocampal formation , neuroscience , fear conditioning , neuroplasticity , psychology , biology , medicine , receptor , synaptic vesicle , amygdala , immunohistochemistry , biochemistry , vesicle , membrane
strategies to upregulate PICALM expression in the vasculature could represent a novel therapeutic target for AD treatment. Methods: 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 Ab load, and behavior were evaluated after treatment. Results: Treatment of Picalm; 5XFADmice with T-65 increased endothelial PICALM levels 2-fold, reduced brain Ab 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 Ab degrading enzymes, as shown by comparable APP, BACE1, soluble APP-b, Neprilysin, and IDE levels in drugand vehicle-treated groups. In 5XFAD mice with endothelial-specific Picalm deletion, no reduction in brain Ab load was observed after treatment. Conclusions: These data indicate that PICALM upregulation in the endothelium with T-65 treatment enhances Ab clearance leading to reduced amyloid load and improved cognitive function in mice. T-65mediated increase in PICALM expression may provide an important new therapeutic avenue for AD.