title: Latrepirdine (Dimebon®), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model.
abstract: Alzheimer disease (AD) is a form of neurodegeneration that develops over the course of multiple decades and as a result of the accumulation of the pathogenic amyloid-β (Aβ) peptide, also known as A4. In late-stage AD, failure of autophagic clearance results in neuronal cell bodies that are almost entirely consumed by autophagic vacuoles (AVs). Previously, we have shown that the potential AD drug latrepirdine (aka Dimebon(®)), a Russian antihistamine that has shown mixed results in phase II clinical trials in AD, regulates metabolism of the amyloid-β/A4 precursor protein (APP). In two Molecular Psychiatry papers in 2012, we sought to determine the mechanism through which latrepirdine regulates APP metabolism and to determine, using an Alzheimer mouse model, whether latrepirdine provides protection from the toxicity associated with the accumulation of Aβ. In cultured cells, we provided evidence that latrepirdine stimulates MTOR- and ATG5-dependent autophagy, leading to the reduction of intracellular levels of APP metabolites, including Aβ. Consistent with this finding, we found that chronic latrepirdine administration resulted in increased levels of the biomarkers thought to correlate with autophagy activation in the brains of TgCRND8 (APP K670M, N671L, V717F) or wild-type mice, and that treatment was associated with abrogation of behavioral deficit, reduction in Aβ neuropathology, and prevention of autophagic failure among TgCRND8 mice.
authors: Elizabeth and Zachary Fisher Center for Alzheimer's Disease Research and Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors: John W
authors: JW
authors: Steele
authors: Sam
authors: S
authors: Gandy
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D007211:Indoles; D051844:alpha-Synuclein; C010119:latrepirdine
keywords: Alzheimer; amyloid; dimebon; latrepirdine; lysosome; macroautophagy; neurodegeneration; presenilin; synuclein; therapeutics