Anterior hypothalamic pathology in Alzheimer’s disease: A human postmortem study using spatial in‐situ proteomics

Abstract

AbstractBackgroundThe anterior hypothalamus contains several sleep‐promoting nuclei, including the suprachiasmatic nucleus (SCN), the key circadian clock in the brain. Sleep disturbances are a common in Alzheimer’s disease (AD), but little is known about the profile of AD‐related pathology in the anterior hypothalamic nuclei.MethodWe used the GeoMx Digital Spatial Profiling (DSP), an in‐situ spatial proteomics platform (Nanostring) to assess spatially resolved tauopathy and tau‐driven protein alteration in the SCN, supraoptic nucleus (SON), and periventricular nucleus (PV) in the anterior hypothalamus of four postmortem brains from three AD subjects and one control. The profiled regions‐of‐interest were confirmed by immunohistochemistry.ResultAll three nuclei showed significantly higher levels of p‐tau 404 and 396 in AD than control, and differential patterns of selective vulnerability for tau, with the SCN, expressing greater p‐tau 404 and 396 levels than the SON. In addition, the p‐tau immunoreactivity corresponds to the DSP data. Interestingly, the PV indicated upregulated β‐amyloid(1‐42) and β‐secretase 1 than others.ConclusionAD patients revealed increased p‐tau expression in the SCN located in the anterior hypothalamus. Given that tau pathology is one of the main features in AD, altered p‐tau level may lead the SCN and other hypothalamic protein alteration shown in this result, influencing the hierarchical clustering. We suggest tauopathy can be a preceding criterion for tau‐driven hypothalamic protein subpopulation, explaining AD‐driven neurodegeneration and dysfunction such as sleep dysregulation in AD.