The paradoxical protective effect of chronic stress on advanced Alzheimer's disease pathology

Core pathology in Alzheimer's disease (AD) includes amyloid-β (Aβ) deposition, gliosis, and eventual neuronal loss. Depression during midlife increases the risk of developing AD at late life. Late-life depression is highly prevalent among AD patients, but its role in AD pathogenesis is unclear, and specifically whether it pushes the brain with established AD pathology towards degeneration. CNS myeloid cells (Microglia and CNS-associated macrophages) clear Aβ early on; however, in advanced disease stages, they adopt a neurotoxic phenotype that exacerbates neurodegeneration. It is unclear whether and how stress and depression influence CNS myeloid cells' dysfunction in AD and the neurodegenerative process.

To investigate the impact of chronic stress on microglial function and on neurodegeneration, we utilized the 5xFAD mouse model, which exhibits extensive Aβ pathology but no neuronal loss at age 7 months, representing a late preclinical AD stage. We used a six-week chronic mild stress (CMS) paradigm to induce depressive behavior, after which CNS myeloid cell activation state was evaluated by transcriptomic analysis, activation marker expression and oxidation function. Neuronal and microglial densities were assessed histologically.

Transcriptomic analysis of freshly isolated CNS myeloid cells showed a basal hyper-activated state in non-stressed 5xFAD mice, whereas CMS suppressed multiple immunologic and metabolic pathways. CMS reduced CD68 expression and reduced oxidative function in CNS myeloid cells. CMS did not induce neurodegeneration in the (behaviorally-relevant) pre-frontal, primary motor, hippocampal and Amygdalar cortices in 5xFAD mice. Rather, CMS protected these regions from microglia-mediated neurodegeneration, caused by a microbial TLR2 agonist.

Chronic stress and depression attenuate CNS myeloid cells. While this has been shown to promote amyloid pathology at early stages, similar attenuation of CNS myeloid cells at the stage of established AD pathology may interfere with their transition into fully neurotoxic microglia, which cause neurodegeneration. These findings highlight the importance of tailoring microglial-targeted therapies to the stage-dependent roles of these cells during AD progression.