Abstract
INTRODUCTION
A higher incidence of dementia, including Alzheimer’s-like pathology, is observed in aged people living with human immunodeficiency virus-1 (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 studies of HIV-1 and AD.
METHODS
We created a novel amyloid precursor protein (APP) (Swedish mutation) knock-in (KI) AD mouse on an immunocompromised NOG background, NOG/APPKM670,671NL/IL-34 (NAIL). Following CD34+ hematopoietic stem cell (HSC) reconstitution, humanized hNAIL mice develop human microglia-like cells in the brain and human immune system in the periphery. This allows, for the first time, studies of progressive brain HIV-1 replication in an AD brain. Four-month-old HSC reconstituted mice were infected with the HIV-1ADA strain, and evaluated at 8 weeks post infection to study the role of brain HIV-1 replication on AD-like pathologies.
RESULTS
HIV-1 replication increased amyloid-beta (Aβ) load in the brain and reduced synaptic and neuronal integrity. Cell type-specific spatial transcriptomic analysis demonstrated that Aβ and HIV-1 drive distinct transcriptional patterns, whereas dual pathology amplified AD-like pathology. Neurons showed the 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.
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This post is Copyright: | September 8, 2026
Neuro-Dementia