Summary This is an “Administrative Supplement Program to Help Develop Alzheimer’s-Focused NIH Grants” in response to NOT-AG-23-032. Emerging neuropathology findings in neuroHIV as well as gene expression results from our group suggest a degree of pathogenic similarity and possibly overlap between neuroHIV and Alzheimer’s Disease (AD). Additionally, the abuse of opioids like heroin, oxycodone and fentanyl and stimulants like cocaine and methamphetamine (METH) is believed to increase the risk of dementias including AD. However, experimental evidence of the detrimental interaction of drugs of abuse and AD are quite limited, particularly in the setting of HIV. To address these knowledge gaps, paralleling and integrating the parent grant, we propose to use in vitro AD models consisting of induced pluripotent stem cells (iPSCs)-derived neural tri-cultures treated with amyloid β 1-42 oligomers and iPCS-derived tri-cultures harboring isogenic APOE alleles, which are key genetic determinants of AD risk and to expose them to either an opioid (morphine) or a stimulant (METH) in the same general design of the parent grant. This Supplement will add AD-focused studies to the experimental design of the parent grant, that does not propose AD/ADRD-focused experiments. This research grant qualifies for the present Supplement under NOT-AG-23-032 because the parent grant is on a related topic (per NOT-AG-23-032): pathogenesis of cognitive decline in neuroHIV and drug abuse comorbidity that are believed to share pathogenic mechanisms and be additive to cognitive decline in AD. The proposed aims closely parallel the parent grant’s with the addition of iPCS models of AD. The parent grant uses iPSCs-derived neural tri-cultures to model HIV-drug abuse interactions but does not propose AD/ADRD- related studies. This Supplement will generate preliminary results for an upcoming R01 application focused on the detrimental interactions of AD with HIV and substance abuse.

Narrative The present Supplement will investigate the detrimental interactions of drugs of abuse and AD with or without concomitant HIV. To this end we will use iPCS-derived neural cultures to model AD in vitro. Ultimately, the proposed experimental-computational approach will result in a better understanding of the molecular mechanisms that are behind the neurodegeneration in HIV, drug abuse, and AD as well as their interactions and will highlight mechanisms of pathogenesis and candidate new therapeutic targets.