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

• Published in: Acta neuropathologica communications Vol. 10; no. 1; pp. 69 - 16
• Main Authors: Murray, Jacinta, Meloni, Gregory, Cortes, Etty P, KimSilva, Ariadna, Jacobs, Michelle, Ramkissoon, Alyssa, Crary, John F, Morgello, Susan
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07.05.2022; BioMed Central; BMC
• Subjects: Advertising executives; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta; Amyloid beta-Peptides - metabolism; Apolipoproteins; Apolipoproteins E - metabolism; Autopsies; Brain; Cloning; Cognition; Frontal Lobe - metabolism; HIV; HIV (Viruses); HIV infection; HIV Infections - complications; HIV Infections - metabolism; HIV Infections - pathology; HIV patients; Human immunodeficiency virus; Humans; Immunohistochemistry; Memory; Microglia; Microglia - pathology; Middle age; Middle Aged; Neurodegeneration; Neurons; Neuropathology; Pathogenesis; Plaque, Amyloid - pathology; Proteins; Risk factors; Tau; tau Proteins - metabolism; Tau; Amyloid beta; HIV; Microglia
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-022-01375-y

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[Formula: see text]) 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[Formula: see text] plaques and neuronal p-tau, and quantitate microgliosis with markers Iba1, CD163, and CD68 in large regions of cortex. Glia in the A[Formula: see text] plaque microenvironment were quantitated by immunofluorescence (IF). The relationship of microgliosis to cognition was evaluated. No relationship between A[Formula: see text] or p-tau accumulation and overall severity of microgliosis was discerned. Individuals with uncontrolled HIV had the greatest microgliosis, but fewer A[Formula: see text] plaques; they also had higher prevalence of APOE [Formula: see text]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[Formula: see text] plaque microenvironment, APOE [Formula: see text]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[Formula: see text] plaque microenvironment, traditional risk factors of AD (APOE [Formula: see text]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[Formula: see text] deposits are established, APOE [Formula: see text]4 predicts increased plaque-associated inflammation.