A selective degeneration of cholinergic neurons mediated by NRADD in an Alzheimer's disease mouse model

Cholinergic neurons in the basal forebrain constitute a major source of cholinergic inputs to the forebrain, modulate diverse functions including sensory processing, memory and attention, and are vulnerable to Alzheimer's disease (AD). Recently, we classified cholinergic neurons into two distinct subpopulations; calbindin D28K-expressing (D28K⁺) versus D28K-lacking (D28K^-) neurons. Yet, which of these two cholinergic subpopulations are selectively degenerated in AD and the molecular mechanisms underlying this selective degeneration remain unknown. Here, we reported a discovery that D28K⁺ neurons are selectively degenerated and this degeneration induces anxiety-like behaviors in the early stage of AD. Neuronal type specific deletion of NRADD effectively rescues D28K⁺ neuronal degeneration, whereas genetic introduction of exogenous NRADD causes D28K^- neuronal loss. This gain- and loss-of-function study reveals a subtype specific degeneration of cholinergic neurons in the disease progression of AD and hence warrants a novel molecular target for AD therapy.