Frontal lobe microglia, neurodegenerative protein accumulation, and cognitive function in people with HIV

Microglia are implicated in Alzheimer's Disease (AD) pathogenesis. In a middle-aged cohort enriched for neuroinflammation, we asked whether microgliosis was related to neocortical amyloid beta A beta deposition and neuronal phosphorylated tau (p-tau), and whether microgliosis predicted cognition. Frontal lobe tissue from 191 individuals autopsied with detectable (HIV-D) and undetectable (HIV-U) HIV infection, and 63 age-matched controls were examined. Immunohistochemistry (IHC) was used to evaluate A beta plaques and neuronal p-tau, and quantitate microgliosis with markers Iba1, CD163, and CD68 in large regions of cortex. Glia in the A beta plaque microenvironment were quantitated by immunofluorescence (IF). The relationship of microgliosis to cognition was evaluated. No relationship between A beta or p-tau accumulation and overall severity of microgliosis was discerned. Individuals with uncontrolled HIV had the greatest microgliosis, but fewer A beta plaques; they also had higher prevalence of APOE epsilon 4 alleles, but died earlier than other groups. HIV group status was the only variable predicting microgliosis over large frontal regions. In contrast, in the A beta plaque microenvironment, APOE epsilon 4 status and sex were dominant predictors of glial infiltrates, with smaller contributions of HIV status. Cognition correlated with large-scale microgliosis in HIV-D, but not HIV-U, individuals. In this autopsy cohort, over large regions of cortex, HIV status predicts microgliosis, whereas in the A beta plaque microenvironment, traditional risk factors of AD (APOE epsilon 4 and sex) are stronger determinants. While microgliosis does not predict neurodegenerative protein deposition, it does predict cognition in HIV-D. Increased neuroinflammation does not initiate amyloid deposition in a younger group with enhanced genetic risk. However, once A beta deposits are established, APOE epsilon 4 predicts increased plaque-associated inflammation.

Automated summary

Microglia play a role in the pathogenesis of Alzheimer's Disease (AD) and are associated with cognitive function. HIV status can predict microgliosis in the cortex, while traditional risk factors of AD have a stronger predictive power in the Aβ plaque microenvironment.