title: Rheb GTPase regulates β-secretase levels and amyloid β generation.
abstract: The β-site amyloid precursor protein (APP)-cleaving enzyme 1 (β-secretase, BACE1) initiates amyloidogenic processing of APP to generate amyloid β (Aβ), which is a hallmark of Alzheimer disease (AD) pathology. Cerebral levels of BACE1 are elevated in individuals with AD, but the molecular mechanisms are not completely understood. We demonstrate that Rheb GTPase (Ras homolog enriched in brain), which induces mammalian target of rapamycin (mTOR) activity, is a physiological regulator of BACE1 stability and activity. Rheb overexpression depletes BACE1 protein levels and reduces Aβ generation, whereas the RNAi knockdown of endogenous Rheb promotes BACE1 accumulation, and this effect by Rheb is independent of its mTOR signaling. Moreover, GTP-bound Rheb interacts with BACE1 and degrades it through proteasomal and lysosomal pathways. Finally, we demonstrate that Rheb levels are down-regulated in the AD brain, which is consistent with an increased BACE1 expression. Altogether, our study defines Rheb as a novel physiological regulator of BACE1 levels and Aβ generation, and the Rheb-BACE1 circuitry may have a role in brain biology and disease.
authors.affiliation: From the Department of Neuroscience, The Scripps Research Institute, Florida, Jupiter, Florida 33458.
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.forename: William
authors.initials: W
authors.lastname: Pryor
authors.forename: Supriya
authors.initials: S
authors.lastname: Swarnkar
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kholodilov
authors.forename: Gopal
authors.initials: G
authors.lastname: Thinakaran
authors.forename: Robert E
authors.initials: RE
authors.lastname: Burke
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Subramaniam
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D000076205:Ras Homolog Enriched in Brain Protein
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D009479:Neuropeptides; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D020559:Monomeric GTP-Binding Proteins
keywords: Aging; Amyloid; GTPase; Protein Stability; Secretases