How do HCN channels play a part in Alzheimer's and Parkinson's disease?

ABSTRACT

Neurodegenerative diseases like Alzheimer's and Parkinson's disease (AD and PD) are well-known, yet their underlying causes remain unclear. Recent studies have suggested that disruption of ion channels contribute to their pathogenesis. Among these channels, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, encoded by HCN1-4 genes, are of particular interest due to their role in generating hyperpolarization-activated current (Ih), which is crucial in various neural activities impacting memory and motor functions. A growing body of evidence underscores the pivotal role of HCN in Aß generation, glial cell function, and ischemia-induced dementia; while HCN is expressed in various regions of the basal ganglia, modulating their functions and influencing motor disorders in PD; neuroinflammation triggered by microglial activation represents a shared pathological mechanism in both AD and PD, in which HCN also plays a significant part. This review delves into the neuronal functions governed by HCN, its roles in the aforementioned pathogenesis, its expression patterns in AD and PD, and discusses potential therapeutic drugs targeting HCN for the treatment of these diseases, aiming to offer a novel perspective and inspire future research endeavors.