title: Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer's progression in vivo.
abstract: Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is produced by β- and γ-cleavages of amyloid β precursor protein (APP). Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme that cleaves ubiquitin at its carboxyl terminal. Dysfunction of UCHL1 has been reported in neurodegenerative diseases. However, whether UCHL1 affects Aβ production and AD progression remains unknown. Here we report that UCHL1 interacts with APP and regulates Aβ production. UCHL1 increases free ubiquitin level and accelerates the lysosomal degradation of APP by promoting its ubiquitination. Furthermore, we demonstrate that overexpression of UCHL1 by intracranial injection of UCHL1-expressing rAAV reduces Aβ production, inhibits neuritic plaque formation and improves memory deficits in AD transgenic model mice. Our study suggests that UCHL1 may delay Alzheimer's progression by regulating APP degradation in a long-term fashion, and that overexpression of UCHL1 may be a safe and effective disease-modifying strategy to treat AD.
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Shuting
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary; C507533:Ubiquitin carboxyl-Terminal Hydrolase L-1, human; D014452:Ubiquitins; D043222:Ubiquitin Thiolesterase