Linking aβ42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model

PLoS Genetics
Yong PingSusan Tsunoda

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 resc...Continue Reading

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Citations

Jan 22, 2019·Expert Opinion on Drug Discovery·Katerina PapanikolopoulouEfthimios Skoulakis
Jan 24, 2020·G3 : Genes - Genomes - Genetics·Grace A ParkerTrudy F C Mackay
Mar 13, 2020·Neurochemical Research·Yan YanHaibing Yu
Jun 28, 2019·Frontiers in Cellular Neuroscience·James P HighamJames J L Hodge
Oct 18, 2019·Nature·Nektarios Tavernarakis
Sep 28, 2018·Molecular Neurodegeneration·Michael DumbacherGerard Griffioen
Feb 10, 2019·International Journal of Molecular Sciences·Roberto MattioliLuciana Mosca
May 25, 2021·Archives of Pharmacal Research·Ajay UpretySoo Young Kim
May 21, 2021·Progress in Neurobiology·S M Courtney, T Hinault
Aug 9, 2019·ACS Chemical Neuroscience·Kristen A StoutGary W Miller

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Methods Mentioned

BETA
transgenic
Transgenics
electrophoresis
PCR

Software Mentioned

Image J
Photoshop
GraphPad Prism
Volocity

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