Department of Psychology, Institute of Neuroscience, University of Oregon, Eugene, OR, USA.
J Alzheimers Dis. 2022;89(4):1385-1402. doi: 10.3233/JAD-220538.
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.
To determine the progression of amyloid pathology throughout the central auditory system and across age in 5XFAD mice.
We quantified intracellular and extracellular antibody labelling of Aβ42 in 6 regions of the central auditory system from p14 to p150.
Pathology appeared first in primary auditory cortex (A1) as intracellular accumulation of Aβ42 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.
These results suggest that Aβ42 accumulation, but not plaques, may impair gap detection.
阿尔茨海默病（AD）的有效治疗将取决于早期发现。这导致了对使用非侵入性测试的早期生物标志物的研究。一个可能的早期生物标志物是听觉时处理缺陷，它反映了中枢听觉通路的功能障碍，并先于 AD 中的认知和记忆下降。间隙检测是一种听觉时处理的测量方法，在人类 AD 中受损，在 AD 的 5XFAD 小鼠模型中也受损。间隙检测缺陷早在 5XFAD 小鼠出生后 60 天就出现，比认知缺陷或细胞死亡早几个月，支持间隙检测作为早期生物标志物。然而，间隙检测缺陷与听觉系统中淀粉样蛋白病理学的进展如何相关仍不清楚。
确定 5XFAD 小鼠中枢听觉系统中淀粉样蛋白病理学的进展和随年龄的变化。
我们从 p14 到 p150 量化了中枢听觉系统 6 个区域中 Aβ42 的细胞内和细胞外抗体标记。
病理学首先出现在初级听觉皮层（A1）中，p21 之前，A1 中第 5 层锥体神经元内的 Aβ42 积累。细胞外斑块较晚出现，在 p90 时，出现在 A1、内侧膝状体和下丘脑中。听觉脑干结构显示出最小的淀粉样蛋白病理学。我们还观察到延髓桥网状核中的病理学，这是脑干结构，不在中枢听觉通路上，但参与听觉惊跳反射。
这些结果表明，Aβ42 积累，而不是斑块，可能会损害间隙检测。
