Linking Aβ42-Induced Hyperexcitability to Neurodegeneration, Learning and Motor Deficits, and a Shorter Lifespan in an Alzheimer’s Model

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Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly population. While it is established that β-amyloid (Aβ) peptide accumulation is a primary even leading to AD, there is little known about how Aβ induces progressive neurodegeneration and decline in cognitive and motor function. Recently, over-production of Aβ has been shown to result in increased neuronal excitability, and Ca2+ “overload”, in hippocampal and cortical neurons. Increased excitability is also consistent with behavioral studies which have shown enhanced seizure activity in mouse models with increased Aβ expression, and increased risk of epilepsy in AD patients. We use a transgenic Drosophila model that expresses the secreted human Aβ42; this Aβ42-Drosophila line exhibits many of the hallmarks of AD. We show that the Aβ42-Drosophila line also displays increased neuronal excitability. We determine that the increase in excitability is due to the degradation of a specific K+ channel, Kv4. We then show that genetic restoration of Kv4 attenuates age-dependent learning and locomotor deficits, slows the onset of neurodegeneration, and partially rescues 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.

Vyšlo v časopise: Linking Aβ42-Induced Hyperexcitability to Neurodegeneration, Learning and Motor Deficits, and a Shorter Lifespan in an Alzheimer’s Model. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005025
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005025

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