CHRNA5links chandelier cells to severity of amyloid pathology in aging and Alzheimer’s Disease

Abstract

Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to cognitive impairment in Alzheimer's Disease (AD). While preclinical work suggests a possible protective and cognitive-enhancing role for the auxiliary nicotinic α5 subunit, mRNA expression of the CHRNA5 gene has not been closely examined in the context of human aging and dementia. Here, we investigate the impact of two common SNPs predicted to have different effects on the nicotinic α5 subunit: the function-compromising rs16969968 and the expression-altering rs1979905. We analyzed data from human prefrontal cortex (922 subjects with matched genotypic and post-mortem RNA sequencing, including 22 subjects with single-nucleus data) of elderly participants in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We tested the impact of SNP haplotypes on prefrontal expression of CHRNA5 as well as that of SNPs in its receptor partners: CHRNA4 and CHRNB2. In the context of cognition and neuropathology, we observed a significant negative association between the high CHRNA5-expressing rs1979905A2 genotype and β-amyloid load in the prefrontal cortex. Our analyses revealed that the greatest abundance of CHRNA5 expression was in chandelier neurons, a sparse but disproportionately-powerful set of interneurons, in addition to layer 5 and 6 pyramidal neurons. In subjects with functionally-unaltered CHRNA5, the proportion of chandelier cells in the prefrontal cortex shows resilience to β-amyloid load, but this resilience is diminished in subjects homozygous for the minor allele of the CHRNA5 missense SNP rs16969968. Taken together, these findings urge further investigation into the role of CHRNA5 and chandelier cells in AD neuroprotection.

Multi-omic integration via similarity network fusion to detect molecular subtypes of ageing

“…RNA Samples were submitted to the Broad Institute’s Genomics Platform for transcriptome library construction following sequencing in three batches using the Illumina HiSeq (batch #1: 50 M 101 bp paired end reads) and NovaSeq6000 (batch #2: 30 M 100 bp paired end; batch#3: 40–50 M 150 bp paired end 121 reads). 32 A cut-off point of 5 for RNA Integrity Number score was used for constructing the cDNA library. 33 The average sequencing depth was 50 million paired reads per sample.…”

Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models

“…Both the TgCRND8 AD mouse and the TgF344 AD rat used here employ human APP mutations [46,55], resulting in amyloid-driven AD pathologies. Amyloid-β directly interacts with nicotinic receptors, though the nature of this interaction is debated and may depend on factors such as concentration, cell type, and nicotinic receptor subunits [111][112][113][114][115][116] with some poised to confer neuroprotection [117,118]. Increases in nicotinic receptor availability may also arise secondary to changes in presynaptic cholinergic release via amyloidβ impairment of choline transport [119][120][121] or choline acetyltransferase [122,123].…”

“…Both the TgCRND8 AD mouse and the TgF344 AD rat used here employ human APP mutations [48,57], resulting in amyloid-driven AD pathologies. Amyloid-β interacts with nicotinic receptors [112][113][114][115][116][117][118][119], the consequences of which depend on cell type and nicotinic receptor configuration. Nicotinic receptors are regulated by many cellular elements, including lynx family proteins [67,120] and protein kinase C by way of muscarinic receptor agonism [62], providing many potential avenues for signalling to be harnessed for compensation.…”