title: Different Expression Patterns of Amyloid-β Protein Precursor Secretases in Human and Mouse Hippocampal Neurons: A Potential Contribution to Species Differences in Neuronal Susceptibility to Amyloid-β Pathogenesis.
abstract: Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer's disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-β protein precursor (AβPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aβ pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aβ deposits in the 10-month-old transgenic mutant human AβPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α-secretase, and its neuroprotective products soluble AβPPα, but low levels of amyloidogenic β-secretase and γ-secretase, and a neurotoxic product, Aβ42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed β-secretase and γ-secretase, but not α-secretase, which could increase Aβ generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48 h following local microinjection of α-secretase antibody ADAM10 into the hippocampus of AβPP/PS1 mice further suggests that high α-secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α-secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AβPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD.
authors.affiliation: Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Xu
authors.affiliation: Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yun-Ying
authors.initials: YY
authors.lastname: Gao
authors.affiliation: Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Rehabilitation Sciences, University of Kentucky Center of Excellence in Rural Health, Hazard, KY, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Marshall
authors.affiliation: Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
authors.forename: Zhi-You
authors.initials: ZY
authors.lastname: Cai
authors.affiliation: Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Xiao
mesh_terms: D000072197:ADAM10 Protein / Q000276:immunology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D013045:Species Specificity; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); C580804:presenilin 1, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000072197:ADAM10 Protein
keywords: Alzheimer’s disease; AβPP/PS1 mice; amyloid-β metabolism; hippocampus