AUDITORY CORTEX DYSFUNCTION AS A NOVEL FEATURE OF ALZHEIMER’S DISEASE NEURODEGENERATION

The clinical association between hearing impairment and cognitive decline is well established. However, the molecular mechanisms underlying the relationship between auditory deprivation and dementia have yet to be fully elucidated. In previous work, we demonstrated that noise-induced hearing loss in an animal model of Alzheimer’s disease (3×Tg-AD mice) accelerates memory deficits and induces synaptic and molecular alterations in the auditory cortex (ACx) and hippocampus (PMID: 34699347).
The present study aims to gain novel mechanistic insights into auditory cortical dysfunctions in Alzheimer’s disease (AD). We found that sound stimulation induces aberrant hyperactivation of ACx neurons, characterized by increased c-Fos expression, together with a marked imbalance in excitatory/inhibitory synaptic markers (vGAT, vGLUT1, and gephyrin) in 3×Tg-AD mice compared with wild-type controls (B6129SF2/J mice) as early as 3 months of age. Furthermore, longitudinal molecular analyses across disease progression (3, 6, 12, and 18 months) demonstrate an age-dependent accumulation of AD pathological markers (including β-amyloid, phosphorylated Tau, BACE-1, and phosphorylated APP) in the ACx of 3×Tg-AD mice, accompanied by progressive synaptic dysfunction, as indicated by reduced PSD-95 and phosphorylated CaMKII expression. Importantly, we identified early auditory memory deficits in 3×Tg-AD mice, emerging at 6 months of age and preceding the onset of spatial and recognition memory impairments typically observed in this model at about 8 months of age.
Collectively, our findings provide novel evidence that AD pathology extends beyond cognitive circuits to involve the auditory system. As such, early auditory cortex alterations are potential biomarkers of dementia.