Linking Ab42-Induced Hyperexcitability to Neurodegeneration, XXXX , and a Shorter Lifespan in an Alzheimer's Model.

@entity1 @entity410 @entity303 @entity73 @entity19 @entity9399 @entity238 @entity2915 @entity179 @entity4207 @entity195 @entity204 @entity528
UNASSIGNED: @entity195 ( @entity195 ) is the most prevalent form of @entity303 in the elderly. b-amyloid (Ab) accumulation in the brain is thought to be a primary event leading to eventual @entity73 in @entity195 . Ab has been shown to promote @entity528 , which is consistent with enhanced @entity410 activity in @entity19 models and @entity195 @entity1 . Little, however, is known about whether, and how, increased excitability contributes to downstream pathologies of @entity195 . Here, we show that overexpression of @entity1 Ab42 in a @entity238 model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, @entity9399 . An age-dependent loss of @entity9399 leads to an increased probability of AP firing. Interestingly, we find that loss of @entity9399 alone results in @entity4207 , as well as a shortened lifespan. To test whether the Ab42-induced @entity528 contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed @entity9399 to near wild-type levels in Ab42-expressing animals. We show that restoration of @entity9399 attenuated age-dependent @entity4207 , slowed the onset of @entity179 , and partially rescued @entity204 seen in Ab42-expressing animals. We conclude that Ab42-induced @entity2915 plays a critical role in the age-dependent cognitive and motor decline of this Ab42- @entity238 model, and possibly in @entity195 .
