Long-read transcriptomics shows synaptic adaptation to amyloid pathology in Alzheimer’s

Abstract

Genome-wide association studies (GWAS) have identified a transcriptional network of Alzheimer's disease (AD) risk genes that are primarily expressed in microglia and are associated with AD pathology. However, traditional short-read sequencers have limited our ability to fully characterize how GWAS variants exert their effects on gene expression regulation or alternative splicing in response to the pathology, particularly resulting in inaccurate detection of splicing. To address this gap, we utilized long-read RNA sequencing in the App NL-G-F knock-in mouse model to identify changes in splicing and novel transcript isoforms in response to amyloid-β. We show that long-read RNA sequencing can recapitulate the expected induction of microglial expressed risk genes such as TREM2 in response to amyloid-β at nine months of age associated with ageing-dependent deficiencies in spatial short-term memory in the App NL-G-F knock-in mice. Our results not only identified novel splicing events and transcript isoforms abundance in genes associated with AD, but also revealed the complex regulation of gene expression through splicing in response to amyloid plaques. Surprisingly, the regulation of alternative splicing (AS) in response to amyloid was seen in genes previously not identified as AD risk genes, expressed in both microglia and neurons, and included genes such as SYNGR1 that modulate synaptic physiology. Our data suggests a model whereby induction of AD risk gene expression associated with microglial proliferation and activation is concomitant with alternative splicing in a different class of genes expressed by microglia and neurons, which act to adapt or preserve synaptic activity in response to amyloid-β during early stages of the disease. Our study provides new insights into the mechanisms and effects of the regulation of genes associated with amyloid pathology, which may ultimately enable better disease diagnosis in the future, and improved tracking of disease progression. Additionally, our findings identify new therapeutic avenues for the treatment opportunities of AD.

Biography

Umran Yaman is a final year PhD student in the John Hardy group at the UK Dementia Research Institute, University College London. Her doctoral research focuses on identifying the genome-wide methylation signature, alternative splicing, and isoform-level changes in response to the amyloid, the earliest phase of Alzheimer's disease.