A novel mechanism underlies pathological, beta-amyloid-induced neuronal hyperexcitation.

摘要

Patients with Alzheimer's disease (AD) exhibit a significantly higher incidence of unprovoked seizures compared to age-matched non-AD controls, and animal models of AD (i.e., transgenic human amyloid precursor protein, hAPP mice) display neural hyper-excitation and epileptic seizures. Hyperexcitation is particularly important because it contributes to the high incidence of epilepsy in AD patients as well as AD-related synaptic deficits and neurodegeneration. Given that there is significant amyloid-beta (Abeta) accumulation and deposition in AD brain, Abeta exposure ultimately may be responsible for neural hyper-excitation in both AD patients and animal models. Emerging evidence indicates that alpha7 nicotinic acetylcholine receptors (alpha7-nAChR) are involved in AD pathology, because synaptic impairment and learning and memory deficits in a hAPPalpha7-/- mouse model are decreased by nAChR alpha7 subunit gene deletion. Given that Abeta potently modulates alpha7-nAChR function, that alpha7-nAChR expression is significantly enhanced in both AD patients and animal models, and that alpha7-nAChR play an important role in regulating neuronal excitability, it is reasonable that alpha7-nAChRs may contribute to Abeta-induced neural hyperexcitation. We hypothesize that increased alpha7-nAChR expression and function as a consequence of Abeta exposure is important in Abeta-induced neural hyperexcitation. In this project, we found that exposure of Abeta aggregates at a nanomolar range induces neuronal hyperexcitation and toxicity via an upregulation of alpha7-nAChR in cultured hippocampus pyramidal neurons. Abeta up-regulates alpha7-nAChRs function and expression through a post translational mechanism. alpha7-nAChR up-regulation occurs prior to Abeta-induced neuronal hyperexcitation and toxicity. Moreover, inhibition of alpha7-nAChR or deletion of alpha7-nAChR prevented Abeta induced neuronal hyperexcitation and toxicity, which suggests that alpha7-nAChRs are required for Abeta induced neuronal hyperexcitation and toxicity. These results reveal a profound role for alpha7-nAChR in mediating Abeta-induced neuronal hyperexcitation and toxicity and predict that Abeta-induced up-regulation of alpha7-nAChR could be an early and critical event in AD etiopathogenesis. Drugs targeting alpha7-nAChR or seizure activity could be viable therapies for AD treatment.