Differences in inflammatory markers, mitochondrial function, and synaptic proteins in male and female Alzheimer's disease post mortem brains

Abstract

Introduction: Inflammation and mitochondrial impairments are suggested to underlie Alzheimer's disease (AD) development. This study examined whether metabolic, synaptic, and inflammatory markers in AD differed from non-demented brains.

Methods: Male and female AD brains were analyzed by immunofluorescence, Western blot, enzyme-linked immunosorbent assay-based cytokine, and mitochondrial respiration analysis.

Results: AD brains had greater Akt phosphorylation, but only AD males had greater downstream mammalian target of rapamycin phosphorylation. AD females showed lower mitochondrial complex IV respiration. AD brains had greater expression of synaptic markers α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, glutamate receptor 1, and synaptophysin, while AD females had a higher expression ELKS1. Microglial expression was lower in AD gray matter, AD females had higher microglial expression in white matter, while cytokine interleukin 2 content was greater in AD brains.

Discussion: Markers of impaired insulin signaling, impaired mitochondrial function, and greater neuroinflammation were found in AD brains. Female brains had greater differences in metabolic signaling than males and this dysregulation is unique/worse with AD.

Highlights: Neuroinflammation and metabolic function are worse with Alzheimer's disease (AD). Female brains exhibit more distinct changes in metabolic signaling than males. Female brains have worse metabolic changes with AD. Harmful inflammatory and mitochondrial signaling may promote AD.

Keywords: Alzheimer's disease; brain metabolism; human brain; inflammation; mitochondria function; sex differences.