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S1–01–01: APOE and APOE receptors in brain lipid metabolism, synaptic functions and clearance of beta‐amyloid
Author(s) -
Bu Guojun
Publication year - 2013
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.2013.04.032
Subject(s) - lrp1 , apolipoprotein e , biology , receptor , endocrinology , neuroscience , medicine , dendritic spine , amyloid beta , microbiology and biotechnology , lipoprotein , ldl receptor , cholesterol , biochemistry , disease , hippocampal formation , peptide
not available. S1-01-04 CHOLESTEROL METABOLITES AS ENDOGENOUS GAMMA-SECRETASE MODULATORS Kevin Felsenstein, Joo-In Jung, Thomas Ladd, Yong Ran, Ashleigh Price, Douglas Galasko, Edward Koo, Gideon Shapiro, Yufei Tang, Guenther Hochhaus, Todd Golde, University of Florida College of Medicine, Gainesville, Florida, United States; University of California San Diego, La Jolla, California, United States; Pharmore, Inc, Gainesville, Florida, United States; University of Florida College of Pharmacy, Gainesville, Florida, United States. Contact e-mail: kfelsenstein0@ufl.edu Background: The use of gamma-secretase modulators (GSMs) remains a promising therapeutic strategy, to selectively lower Abeta42, for the prevention of Alzheimer’s disease (AD). To identify anti-Abeta therapies safe enough to use in prevention studies, we explored whether there are endogenous metabolites that may potentially function as GSMs. Based on studies showing that cholesterol regulates gamma-secretase activity and binds APP at a site potentially involved in modulating gamma-secretase processivity, we focused our studies on the acidic oxysterols. There is an ever increasing body of evidence indicating that these oxysterols are more than just intermediates of metabolic pathways. Methods: Using cell based assays, in vitro screens, APP animal models, and specific cytochrome P450 knockout mice we have explored how various acidic, and structurally related non-acidic, sterols regulate Abeta42 production. Results:We find that sterol carboxylates or acidic oxysterols represent a potential novel class of GSM with a potency range of 0.2-10 mM. Of these cholestenoic acid (CA) with an Abeta42 lowering IC50 1⁄4 w0.2 mM was the most potent. As Cyp27a1 and Cyp7b1 enzymes are key regulators of CA metabolism, we have begun studies of knockout mice that lack these enzymes. Cyp7b1-/mice show a significant reduction in brain Ab42:Ab38 consistent with predicted increases in CA in these mice. Ongoing studies are examining Abeta and CA levels in these knockout lines and in various paradigms where CA levels might be altered either genetically or biochemically. Conclusions: These data indicate that CA and potentially other bile acids may function as