Neuropathologic and proteomic analysis of human hippocampal CA1 pyramidal neuron sublayers in human Alzheimer’s disease

Abstract

AbstractHippocampal area CA1 is vulnerable to Alzheimer’s disease (AD) pathology, but if and how CA1 pyramidal neuron (PN) subpopulations are impacted is unclear. Specifically, CA1 PNs can be divided into a superficial (sPN) and deep (dPN) layer that have distinct molecular and functional properties. Understanding AD pathophysiology at the level of these CA1 PN subpopulations may inform on mechanisms of vulnerability and cognitive dysfunction. We first quantified amyloid plaque and tau pathology in Braak stage V-VI human AD cases, revealing that the sPN layer shows much higher levels of AD pathology compared to the dPN layer. We then performed quantitative localized proteomics of sPN and dPN layers in Braak stage VI human AD cases, which revealed that the two layers show disease- and function-related molecular differences that support relative hyperexcitability of sPNs and markers of delayed neurodegeneration in dPNs. In sum, these findings support that sPNs are differentially vulnerable in human AD.