Spatiotemporal transcriptomic dynamic across the auditory pathway from young to old age in 5xFAD Alzheimer disease mice

Abstract

Auditory dysfunction can precede clinical dementia, but the molecular progression of Alzheimer disease (AD) pathology from the sensory periphery to auditory cortex remains poorly resolved. We performed bulk RNA sequencing of auditory cortex (AC), inferior colliculus (IC), cochlear nucleus (CN), and cochlea from 5xFAD and wild-type mice at postnatal day 50 (P50), 8 months, 11 months, and 16 months. Age-specific genotype effects and Genotype x Age interactions were evaluated using DESeq2, followed by Hallmark, KEGG, and Gene Ontology gene-set enrichment analyses and a cross-region synthesis of interaction trajectories. At P50, AC, IC, and cochlea showed coordinated suppression of mitochondrial metabolism, translation, RNA processing, and proteostasis, whereas CN displayed the opposite metabolic and biosynthetic profile together with reduced synaptic and adhesion programs. At 8 months, inflammatory interactions converged across all four regions, including interferon, complement, IL6-JAK-STAT3, and broader immune-response pathways. This coordination fractured at 11 months: AC and IC retained inflammatory and negative synaptic shifts, whereas CN and cochlea frequently changed in the opposite direction, including transient positive shifts in synaptic programs. By 16 months, immune interactions converged again, while metabolic, proteostatic, and synaptic trajectories remained region dependent; CN opposed AC, IC, and cochlea in several major metabolic programs. These findings define a distributed, asynchronous response rather than a monotonic bottom-up or top-down progression. The resulting spatiotemporal map links early metabolic stress, intermediate central-peripheral decoupling, and late inflammatory convergence, providing a molecular framework for evaluating peripheral to central auditory gain and temporal-processing measures as candidate indicators of AD progression.