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<p>Hearing loss is a major modifiable risk factor for Alzheimer’s disease (AD), but how auditory deprivation engages specific neural circuits, particularly in a sex-dependent manner, to promote amyloid pathology remains unclear. We examined whether sound deprivation alters amyloid-beta (Aβ) deposition, auditory neural activity, and cognition in 5xFAD mice. Notably, sound deprivation using bilateral earplugging from 2 to 4 months selectively increased Aβ plaque burden in the inferior colliculus (IC) of female 5xFAD mice, with no comparable effect in males. This IC-selective pathology was accompanied by increased c-Fos expression in the IC. Microglial density was unchanged, but earplugging increased the fraction of plaque-associated microglia and reduced microglia–plaque distance specifically in the IC, suggesting local amplification of AD-related pathology at the plaque interface. 5xFAD mice without deprivation retained intact novel object recognition (NOR) at 6 months. In contrast, female 5xFAD mice with prior earplugging developed a selective NOR deficit despite no detectable increase in hippocampal plaque burden, whereas males remained unaffected. Together, these findings identify the IC as a female-vulnerable locus where transient sound deprivation drives persistent auditory-circuit hyperactivity, remodels microglia–plaque interactions, and accelerates region-specific amyloid pathology with extra-hippocampal cognitive consequences, highlighting sensory loss as modifiable risk factor in prodromal AD.</p>

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Hearing loss drives region-specific amyloid accumulation along the auditory pathway in female 5xFAD mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Jiwon Park,
  • Se Yeon Jeong,
  • Jun Hee Kim

摘要

Hearing loss is a major modifiable risk factor for Alzheimer’s disease (AD), but how auditory deprivation engages specific neural circuits, particularly in a sex-dependent manner, to promote amyloid pathology remains unclear. We examined whether sound deprivation alters amyloid-beta (Aβ) deposition, auditory neural activity, and cognition in 5xFAD mice. Notably, sound deprivation using bilateral earplugging from 2 to 4 months selectively increased Aβ plaque burden in the inferior colliculus (IC) of female 5xFAD mice, with no comparable effect in males. This IC-selective pathology was accompanied by increased c-Fos expression in the IC. Microglial density was unchanged, but earplugging increased the fraction of plaque-associated microglia and reduced microglia–plaque distance specifically in the IC, suggesting local amplification of AD-related pathology at the plaque interface. 5xFAD mice without deprivation retained intact novel object recognition (NOR) at 6 months. In contrast, female 5xFAD mice with prior earplugging developed a selective NOR deficit despite no detectable increase in hippocampal plaque burden, whereas males remained unaffected. Together, these findings identify the IC as a female-vulnerable locus where transient sound deprivation drives persistent auditory-circuit hyperactivity, remodels microglia–plaque interactions, and accelerates region-specific amyloid pathology with extra-hippocampal cognitive consequences, highlighting sensory loss as modifiable risk factor in prodromal AD.