Accelerated amyloid neurodegeneration in HIV-1-infected APP-KI Alzheimer’s disease mice
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INTRODUCTION
A higher incidence of dementia, including Alzheimer ’s-like pathology, is observed in aged people living with HIV-1. However, mechanisms linking HIV-1 to Alzheimer’s disease (AD) pathology remain unclear, due to the lack of animal models that allow for concurrent study.
METHODS
We created a novel APP knock-in (KI) AD mouse, NOG/APP KM670,671NL /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-1 ADA strain facilitated studies of HIV-1 replication on AD pathologies.
RESULTS
HIV-1 replication increased Aβ levels and reduced synaptic and neuronal integrity. Spatial transcriptomics demonstrated distinct Aβ 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.
DISCUSSION
The hNAIL mice enable interrogation of HIV-AD comorbidities, with a future potential for the development of novel therapeutic interventions.
