Proteolytic cleavage of constitutively expressed proteins can generate peptides with novel bioactive properties. Matrix metalloproteinase (MMP)-2 cleaves the 4 amino-terminal residues of the chemokine, stromal cell-derived factor (SDF)-1␣, yielding a highly neurotoxic molecule, SDF(5-67), which fails to bind to its cognate receptor, CXCR4. Herein, we detected SDF(5-67) in brain monocytoid cells of HIV-infected persons, particularly in those with HIV-associated dementia. SDF(5-67) activated cell type-specific expression of proinflammatory genes including IL-1␤, TNF␣, indoleamine 2,3-dioxygenase (IDO), and IL-10 in both astrocytic and monocytoid cells (P < 0.05). Unlike SDF-1␣, SDF(5-67) caused neuronal membrane perturbations with ensuing neurotoxicity and apoptosis (P < 0.05) through engagement of an inducible receptor. CXCR3 antagonists and siRNA-mediated knockdown of CXCR3 inhibited SDF(5-67)-stimulated neurophysiological changes, neuronal death, and neuroimmune activation (P < 0.05). Moreover SDF(5-67) bound directly to CXCR3 in a competitive manner, mediated by its amino terminus. In vivo neuroinflammation, neuronal loss, and neurobehavioral abnormalities caused by SDF(5-67) (P < 0.05) were prevented by a CXCR3 antagonist. These studies reveal additive neuropathogenic properties exerted by a proteolytically cleaved chemokine as consequences of a change in receptor specificity, culminating in neurodegeneration.apoptosis ͉ chemokine ͉ human immunodeficiency virus ͉ neuron ͉ stromal cell-derived factor-1␣

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Objective We report a gene x environment (health) study focusing on concurrent performance and longitudinal change in a latent-variable executive function (EF) phenotype. Specifically, we tested the independent and interactive effects of a recently identified insulin degrading enzyme genetic polymorphism (IDE rs6583817) and pulse pressure (PP) (one prominent aging-related vascular health indicator) across up to 9 years of EF data in a sample of older adults from the Victoria Longitudinal Study. Both factors vary across a continuum of risk-elevating to risk-reducing and have been recently linked to normal and impaired cognitive aging. Method We assembled a genotyped and typically aging group of older adults (n=599, M age=66 years at baseline), following them for up to three longitudinal waves (M interval=4.4 years). We used confirmatory factor analyses, latent growth modeling, and path analyses to pursue three main research goals. Results First, the EF single factor model was confirmed as comprised of 4 executive function tasks and it demonstrated measurement invariance across the waves. Second, older adults with the major IDE G allele exhibited better EF outcomes than homozygotes for the minor A allele at the centering age of 75 years. Adults with higher PP performed more poorly on EF tasks at age 75 years and exhibited greater EF longitudinal decline. Third, gene x health interaction analyses showed that worsening vascular health (higher PP) differentially affected EF performance in older adults with the IDE G allele. Discussion Genetic interaction analyses can reveal differential and magnifying effects on cognitive phenotypes in aging. In the present case, pulse pressure is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across the risk and protective allelic distribution of this IDE gene.

Genetic polymorphisms of Catechol-O-methyltransferase (COMT) and Brain-derived neurotrophic factor (BDNF) have shown promising but inconsistent linkages with executive function (EF) in normal aging. We tested (a) independent contributions of COMT and BDNF risk, (b) potential magnification by risk-related interactions or additive effects with age, and (c) effect modification through stratification by Apolipoprotein E (APOE; risk (ε4+)). Multiple linear regression models were applied with non-demented older adults (N = 634; range: 53–95 years) for an EF latent variable. No independent effects of BDNF or COMT on EF were observed. Additive (but not interactive) effects of COMT, BDNF, and age showed that older adults with a high-risk allelic combination performed differentially worse. Of two tested models of synergistic effects, the additive approach selectively supported a magnification hypothesis, which was qualified by the presence or absence of APOE ε4.