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.
Highlights
The accumulation of β-amyloid (Aβ) oligomers in the brain has strongly been implicated as a primary event in the progression of Alzheimer’s disease (AD) [1,2,3,4]
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
While many studies have shown that Aβ induces excitatory synaptic depression [5,6], more recent reports suggest that Aβ expression leads to neuronal hyperactivity in cortical and hippocampal neurons [7,8,9,10,11,12,13]
Summary
The accumulation of β-amyloid (Aβ) oligomers in the brain has strongly been implicated as a primary event in the progression of Alzheimer’s disease (AD) [1,2,3,4]. While many studies have shown that Aβ induces excitatory synaptic depression [5,6], more recent reports suggest that Aβ expression leads to neuronal hyperactivity in cortical and hippocampal neurons [7,8,9,10,11,12,13]. While increased excitability is consistent with enhanced seizure activity in Aβ expressing mouse models [7,11] and increased risk of epilepsy in AD patients [14], it is unknown whether, and to what extent, hyperactivity contributes to downstream effects associated with Aβ accumulation, such as impaired cognitive and motor function. An increase in spike afterdepolarization has been reported in CA1 pyramidal neurons from transgenic mice overexpressing Aβ [13]. A transgenic mouse line expressing high levels of human Aβ has been reported to have decreased levels of the voltage-gated Na+ channel, Nav1.1, in parvalbumin inhibitory interneurons [15]
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