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Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disease of aging characterized by the presence in the brain of neurofibrillary tangles and senile plaques, the latter being composed of amyloid beta (Aβ) peptides. Aβ is implicated in synapse dysfunction and neuronal cell death, ultimately leading to the cognitive decline seen in the disease. Significant research effort has therefore focused on studying the production and clearance mechanisms of Aβ. Sequential cleavage of Amyloid Precursor Protein (APP) by β- and γ-secretase activities releases the Aβ peptide. β-site APP-Cleaving Enzyme 1 (BACE1) was identified as the β-secretase over 15 years ago, and is an attractive therapeutic target for treatment of AD. Modulating BACE1 localization away from the intracellular compartment in which it encounters APP is one proposed strategy for specifically blocking APP cleavage, leaving the other functions of BACE1 intact. However, a detailed characterization of BACE1 transport, specifically in neurons, is incomplete. I set out to study the potential mediators of BACE1 localization in neurons, focusing on a type of post-translational modification, palmitoylation. I hypothesized that BACE1 mislocalization in neurons would alter APP processing and Aβ deposition. Using cultured hippocampal neurons expressing a non-palmitoylatable mutant, I have found that lack of palmitoylation prevents BACE1 localization in dendritic spines. While BACE1 normally enriches into the axonal versus the somatodendritic compartment over time in mature neurons, the non-palmitoylatable mutant does not. I have created a knock-in mouse model in which the non-palmitoylatable mutant is expressed under the control of the endogenous promoter, and while this mouse thus far has failed to demonstrate any striking differences in BACE1 localization or APP processing compared to mice expressing wild-type BACE1, an Alzheimer’s mouse model expressing this non-palmitoylatable mutant exhibits decreased Aβ plaque deposition. This mouse model therefore constitutes a valuable tool to study whether specific modifications of BACE1 affect transport in vivo and whether this transport is linked to APP processing.

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