Brain Region Specific Association of Microtubule‐Associated Protein 2 with Inflammatory and Growth Factor Gene Expression

Abstract

Microtubule‐associated protein 2 (MAP2) expression is directly correlated with neurocognitive impairment in subjects with HIV‐associated neurocognitive disorder (HAND). Our previous microarray analysis of hippocampal tissue, identified alterations in immune response and neurogenesis as potential mechanisms contributing to cognitive deficits in chronic binge alcohol (CBA)‐administered, simian immunodeficiency virus (SIV)‐infected macaques. The aim of this study was to determine whether expression of inflammatory genes and growth factor genes were associated with differential MAP2 expression in brain regions associated with HAND. Adult, male rhesus macaques were fitted with intra‐gastric catheters for chronic binge alcohol (CBA, 13–14 g EtOH/kg/week, n = 8) or sucrose (SUC, n = 7) administration beginning three months prior to SIV infection and continuing through the duration of the study until animals reached end‐stage disease criteria (range from 3 to 24 months post‐inoculation). Following euthanasia, brains were excised and pre‐frontal cortex (PFC), caudate (CD), and hippocampus (HP) tissue were isolated and used for qPCR quantification of inflammatory and growth factor genes, and viral loads. We utilized R statistical software to build regression models using the all‐subsets technique with gene expression, viral load, CBA, and time to end‐stage as predictor variables for MAP2 expression. In the PFC, growth factors BDNF and IGFBP5, along with time to end‐stage by CBA interaction were significantly associated with MAP2 expression. In the CD, growth factors IGFBP5 and MAPK1, inflammatory cytokines ISG15, IL6, and TNF, and time to end‐stage were significantly associated with MAP2 expression. In the HP, the growth factor MAPK1, inflammatory cytokine IL6, and brain viral load were significantly associated with MAP2 expression. These results indicate brain region specific relationships between growth factor and inflammatory cytokine expression with MAP2, a molecular marker of cognitive impairment. PFC MAP2 associated with growth factors and showed greater susceptibility to an alcohol‐SIV interaction. In the subcortical structures, CD and HP, MAP2 expression associated with inflammation. Different treatments may be necessary for HAND subjects with cortical compared to subcortical cognitive impairments.Support or Funding InformationP60AA09803, T32AA07577, F31AA024365