Abstract
Our previous findings demonstrated that astrocytic HIF‐1α plays a major role in HIV‐1 Tat‐mediated amyloidosis which can lead to Alzheimer's‐like pathology‐a comorbidity of HIV‐Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV‐1 Tat stimulated astrocyte‐derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF‐1α could likely mitigate HIV‐1 Tat‐ADEV‐mediated neuronal injury. Rat hippocampal neurons when exposed to HIV‐1 Tat‐ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF‐1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV‐1 Tat‐ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV‐1 Tat‐ADEVs, exhibited behavioural changes, and Alzheimer's ’s‐like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF‐1α silenced ADEVs. This is the first report demonstrating the role of amyloid‐carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF‐1α.
This study showed that HIV‐1 Tat upregulates EV biogenesis, release & amyloid cargoes in ADEVs, which upon being uptaken by the neurons leads to amyloid & pTau accumulation resulting in synaptodendritic injury. When these Tat‐ADEVs were injected in the naïve mice brain, behavioral changes, Alzheimer's like pathology & synaptodegeneration was observed. Intriguingly, HIF‐1α silenced ADEVs demonstrated neuroprotective effects, thus underscoring the protective role of HIF‐1α silencing.