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

Abstract

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

Neuronal accumulation of hyperphosphorylated tau protein predicts stable memory impairment in people living with HIV

“…Whereas 39% described intravenous drug use (IVDU) as an HIV risk, 85% endorsed a lifetime substance use disorder (SUD). At autopsy, 58% had p-tau containing neurons in their brain, and 29% parenchymal Aβ plaque; as published previously, the majority of plaques were diffuse, and both pathologies were generally modest in the majority of brains analyzed [18]. In the 78 individuals displaying neuronal p-tau, distribution was restricted to entorhinal cortex in 35%, extended into hippocampal formation in 23%, and was neocortical in 42%.…”

“…We also demonstrated associations between APOE allele status, age, duration of HIV disease and Aβ deposition, and between diabetes mellitus and neuronal p-tau. In these studies, neuroinflammation did not show a predictive effect for abnormal protein deposition [18,28]. The current study used a smaller sample and was focused on determining the contributions of Aβ and p-tau to cognitive impairments; in establishing these relationships, we also found that HIV-associated variables (viremia and duration of HIV disease) and comorbidities (SUD, WRAT-3 reading levels, and diabetes) contributed to cognitive outcomes, highlighting the complexity of neurobehavioral outputs, which transcend a single protein deposition or clinical factor.…”

“…This has created a unique paradigm for 'person-specific' pathology, as there is potential for HIV to cause central nervous system (CNS) damage in concert with aging and neurodegeneration. Whereas virally-mediated neuroinflammation accounts for HIV-associated neurocognitive disorders (HAND) in individuals lacking benefits of cART, a residuum of generally milder neuropsychological impairment without similarly robust neuroinflammation has become apparent in treated populations [17][18][19]. As the basis of cART-era deficits is unclear, there is interest in the potential contributions of Ab and p-tau pathologies to HIV-associated neuropsychological phenotypes [20][21][22][23][24].…”

Complement component 3 and complement factor H protein levels are altered in brain tissues from people with human immunodeficiency virus: A pilot study

“…However, this translates to increased susceptibility to age-related neuropathogenesis such as Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI) ( Althoff et al, 2022 ). Indeed, multiple studies from independent labs have implicated age-related proteinopathies in neuropathogenesis in PWH ( Achim et al, 2009 ; Gisslen et al, 2009 , 2019 ; Chen et al, 2014 ; Fields et al, 2018 , 2020 ; Murray et al, 2022 ). Consequently, there is a need to better understand mechanisms of age-related neuropathogenesis in PWH.…”

“…In a study of frontal cortex (FC) samples from PWH, Aβ plaques were detected in 29% of 279 cases ( Umlauf et al, 2019 ). To date, numerous studies have provided evidence of AD-related neuropathogenesis in HIV ( Chen et al, 2014 ; Fields et al, 2018 ; Gisslen et al, 2019 ; Chemparthy et al, 2021 ; Murray et al, 2022 ), and thus, there is a need to better understand the common neuropathogenic mechanisms in AD and HAND.…”