title: Linking aβ42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model.
abstract: Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly. β-amyloid (Aβ) accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. Aβ has been shown to promote neuronal hyperactivity, which is consistent with enhanced seizure activity in mouse models and AD patients. Little, however, is known about whether, and how, increased excitability contributes to downstream pathologies of AD. Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. Interestingly, we find that loss of Kv4 alone results in learning and locomotion defects, as well as a shortened lifespan. To test whether the Aβ42-induced increase in neuronal excitability contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed Kv4 to near wild-type levels in Aβ42-expressing animals. We show that restoration of Kv4 attenuated age-dependent learning and locomotor deficits, slowed the onset of neurodegeneration, and partially rescued premature death seen in Aβ42-expressing animals. We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ping
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Eu-Teum
authors.initials: ET
authors.lastname: Hahm
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Girma
authors.initials: G
authors.lastname: Waro
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Dai-An
authors.initials: DA
authors.lastname: Vo-Ba
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Ashley
authors.initials: A
authors.lastname: Licursi
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Han
authors.initials: H
authors.lastname: Bao
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Logan
authors.initials: L
authors.lastname: Ganoe
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Finch
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Tsunoda
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051672:Shal Potassium Channels / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D051672:Shal Potassium Channels; C075222:amyloid beta-protein (1-42); D046988:Proteasome Endopeptidase Complex