CHRNA5links chandelier cells to protection against amyloid pathology in human aging and Alzheimer's Disease

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 geneCHRNA5and the impact of relevant single nucleotide polymorphisms (SNPs) in prefrontal cortex from 922 individuals with matched genotypic and postmortem RNA sequencing in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We find that a genotype robustly linked to expression ofCHRNA5(rs1979905A2) predicts significantly reduced cortical β-amyloid load. Yet, co-expression analysis shows a clear dissociation between expression ofCHRNA5and 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-elevatedCHRNA5expression 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 from 549 individuals demonstrates that chandelier cells have increased amyloid vulnerability in individuals homozygous for the missenseCHRNA5SNP (rs16969968A2) that impairs function/trafficking of nicotinic α5-containing receptors. These findings suggest thatCHRNA5and its nicotinic α5 subunit exert a neuroprotective role in aging and Alzheimer's disease potentially centered on chandelier interneurons.