Accelerated amyloid neurodegeneration in HIV-1-infected APP-KI Alzheimer's disease mice

Abstract

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSA higher incidence of dementia, including Alzheimer s-like pathology, is observed in aged people living with HIV-1. However, mechanisms linking HIV-1 to Alzheimers disease (AD) pathology remain unclear, due to the lack of animal models that allow for concurrent study. METHODSWe created a novel APP knock-in (KI) AD mouse, NOG/APPKM670,671NL/IL-34 (hNAIL) that permits study of progressive brain HIV-1 replication. The mice harbor human microglia-like cells. Four-month-old CD34+ human cell reconstituted mice infected with the HIV-1ADA strain facilitated studies of HIV-1 replication on AD pathologies. RESULTSHIV-1 replication increased A{beta} levels and reduced synaptic and neuronal integrity. Spatial transcriptomics demonstrated distinct A{beta} and HIV-1 transcriptional patterns, whereas dual diseased combinations amplified AD pathology. Neurons showed highest transcriptional change, with genes linked to neuroinflammation, protein trafficking, and synaptic dysfunction. DISCUSSIONThe hNAIL mice enable interrogation of HIV-AD comorbidities, with a future potential for the development of novel therapeutic interventions.