CHRNA5 links chandelier cells to protection against amyloid pathology in human aging and Alzheimer's Disease

Abstract

Abstract Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to neuropathology in Alzheimer’s Disease (AD). Protective and cognitive-enhancing roles for the nicotinic α5 subunit have been identified, but this gene has not been closely examined in the context of human aging and dementia. Therefore, we investigate the nicotinic α5 gene CHRNA5 and the impact of relevant single nucleotide polymorphisms (SNPs) in prefrontal cortex from 922 individuals with matched genotypic and post-mortem RNA sequencing in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We find that a genotype robustly linked to expression of CHRNA5 (rs1979905A2) predicts significantly reduced β-amyloid load in prefrontal cortex. Yet, co-expression analysis shows a clear dissociation between expression of CHRNA5 and other cholinergic genes, suggesting a distinct cellular expression profile for the human nicotinic α5 subunit. Consistent with this prediction, single nucleus RNA sequencing from 22 individuals reveals disproportionately-elevated CHRNA5 expression in chandelier cells. These interneurons are enriched in amyloid-binding proteins and also play a vital role in excitatory/inhibitory (E/I) balance. Cell-type proportion analysis demonstrates that chandelier cells have increased amyloid vulnerability in individuals homozygous for the missense CHRNA5 SNP (rs16969968A2) that impairs function/trafficking of nicotinic α5-containing receptors. These findings suggest that CHRNA5 and its nicotinic α5 subunit exert a neuroprotective role in aging and Alzheimer's disease potentially centered on chandelier interneurons.