Amyloid Pathology in the Central Auditory Pathway of 5XFAD Mice Appears First in Auditory Cortex

Background: Effective treatment of Alzheimer's disease (AD) will hinge on early detection. This has led to the search for early biomarkers that use non-invasive testing. One possible early biomarker is auditory temporal processing deficits, which reflect central auditory pathway dysfunction and precede cognitive and memory declines in AD. Gap detection is a measure of auditory temporal processing, is impaired in human AD, and is also impaired in the 5XFAD mouse model of AD. Gap detection deficits appear as early as postnatal day 60 in 5XFAD mice, months before cognitive deficits or cell death, supporting gap detection as an early biomarker. However, it remains unclear how gap detection deficits relate to the progression of amyloid pathology in the auditory system. Objective: To determine the progression of amyloid pathology throughout the central auditory system and across age in 5XFAD mice. Methods: We quantified intracellular and extracellular antibody labelling of A beta(42) in 6 regions of the central auditory system from p14 to p150. Results: Pathology appeared first in primary auditory cortex (A1) as intracellular accumulation of A beta(42) in layer 5 pyramidal neurons by age p21. Extracellular plaques appeared later, by age p90, in A1, medial geniculate body, and inferior colliculus. Auditory brainstem structures showed minimal amyloid pathology. We also observed pathology in the caudal pontine reticular nucleus, a brainstem structure that is outside of the central auditory pathway but which is involved in the acoustic startle reflex. Conclusion: These results suggest that A beta(42) accumulation, but not plaques, may impair gap detection.

Automated summary

The research found that amyloid pathology in 5XFAD mice starts with intracellular accumulation of A beta(42) in the primary auditory cortex (A1) before progressing to extracellular plaques in A1 and other central auditory system regions. Gap detection deficits in 5XFAD mice appear earlier than cognitive deficits and may be related to the accumulation of A beta(42).