%0 Journal Article
%T Linking A¦Â42-Induced Hyperexcitability to Neurodegeneration, Learning and Motor Deficits, and a Shorter Lifespan in an Alzheimer¡¯s Model
%A Ashley Licursi
%A Dai-An Vo-Ba
%A Eu-Teum Hahm
%A Girma Waro
%A Han Bao
%A Kelly Finch
%A Logan Ganoe
%A Qian Song
%A Susan Tsunoda
%A Yong Ping
%J -
%D 2015
%R 10.1371/journal.pgen.1005025
%X Alzheimer¡¯s disease (AD) is the most prevalent form of dementia in the elderly. ¦Â-amyloid (A¦Â) accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. A¦Â 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 A¦Â42 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 A¦Â42-induced increase in neuronal excitability contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed Kv4 to near wild-type levels in A¦Â42-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 A¦Â42-expressing animals. We conclude that A¦Â42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this A¦Â42-Drosophila model, and possibly in AD
%K Neurons
%K Larvae
%K Alzheimer's disease
%K Membrane potential
%K Proteasomes
%K Drosophila melanogaster
%K Fructoses
%K Human learning
%U https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005025