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[P3–159]: INTRANASAL INTERVENTION OF THE LXRS‐APOE‐MICROGLIA AXIS TO IMPROVE BRAIN BETA‐AMYLOID CLEARANCE IN A TRANSGENIC MOUSE MODEL OF AD
Author(s) -
Navas Guimaraes Maria Eugenia,
Bistue Millon Maria Beatriz,
FernandezMegia Eduardo,
Cuello A Claudio,
Bruno Martin Alejandro
Publication year - 2017
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.2017.06.1371
Subject(s) - neuroinflammation , genetically modified mouse , medicine , apolipoprotein e , amyloid beta , transgene , liver x receptor , pharmacology , neuroscience , chemistry , inflammation , biology , nuclear receptor , disease , biochemistry , gene , transcription factor
components within axons, little is known about these mechanisms. One possible mechanism by which transport defects can occur is by improper regulation of molecular motors. Methods:Previous work has shown that reduction of Presenilin (PS) or Glycogen synthase kinase-3b (GSK-3b) stimulated the axonal motility of APP vesicles. Excess GSK-3b causes axonal transport defects and increased motor binding to membranes. Reduction of PS decreased active GSK-3b and motor binding to membranes, suggesting that PS and GSK-3b may function together during axonal transport. Since PS and GSK3b are known to interact in the b-Catenin pathway, we hypothesize that PS influences GSK3b activity for motor regulation. Using Drosophila genetics, we found that excess PS rescued GSK-3bmediated axonal blockages. Results:Intriguingly, the catalytic region of PS (PS loop), which is known to bind to GSK3b, is essential for this rescue. Disruption of PS loop (PSDE9) exacerbated GSK3b-mediated axonal blocks, while excess of PS loop suppressed it. Conclusions:Together, our observations suggest that functional PS containing an intact PS loop region is required to modulate GSK-3b-mediated roles during axonal transport. Perhaps, PS and GSK-3b physically interact to regulate motor activity during axonal transport similar to GSK-3b-mediated mechanisms in the b-Catenin pathway.