ErbB4 In PV Neurons Mediates A?-induced Neurotoxicity:Implications For Alzheimeri's Disease

Alzheimer's disease(AD)is a common neurodegenerative disease affecting cognitive function in the elderly population.Abnormal accumulation of amyloid p(Ap)in the brain is the major initial factor for AD.However,the mechanisms underlying A?-induced neuropathology is remain unclear.Ap causes the decrease of synaptic glutamatergic transmission but also induces the aberrant neural network activity in AD model mice.The seemingly contradictory phenomenon may be due to GABAergic inhibitory intemeuron deficits in AD.However,the mechanism of GABAergic dysfunction remains to be further studied.ErbB4 is a receptor tyrosine kinase expressed in GABAergic inhibitory intemeuron and especially in PV intemeuron.It is crucial for the GABAergic and PV intemeuron's development and function.However,whether ErbB4 in PV interneurons is associated with A?-induced neuropathology remains unknown.In this study,we found that ErbB4 interacted with A?/APP by immunstaining,co-immunoprecipitation and pull down.Moreover,Ap increased the level of pErbB4.In order to further study the function of ErbB4 during AD,we used a Cre-floxp strategy to get non-AD and AD model which ErbB4 was deleted or not in PV interneurons.We found that ablation of ErbB4 inhibited A?-induced LTP reduction.This suggested that ErbB4 mediated A?-induced neurotoxicity.Furthermore,deletion of ErbB4 reversed the LTP deficits in hAPP-J20 mice.Morris water maze test showed that ErbB4 deletion rescued the deficits of spatial memory in hAPP-J20 mice.However,deletion of ErbB4 in PV neurons did not affect the Ap deposition and the proteolytic processing of hAPP in the cortex and hippocampus of hAPP-J20 mice.Therefore,our results suggested that ErbB4 might mediate Ap-induced neuropathology via its interaction with Ap.ErbB4 in PV neurons played an important role in the deficits of synapatic plasticity and spatial memory in hAPP-J20.Targeting A?-ErbB4 interaction could be a potential candidate to interfere A?-induced neurotoxicity and the progress of AD pathogenesis.