Anti-HIV drugs promote β-amyloid deposition and impair learning and memory in BALB/c mice

Objectives: Growing evidence suggested that antiretroviral (ARV) drugs may promote amyloid beta (A beta) accumulation in HIV-1-infected brain and the persistence of HIV-associated neurocognitive disorders (HANDs). It has also been shown that lipid peroxidation upregulates beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) expression and subsequently promotes A beta peptide production. In the present study, we examined whether chronic exposure to the anti-HIV drugs tenofovir disoproxil fumarate (TDF) and nevirapine induces lipid peroxidation thereby promoting BACE1 and A beta generation and consequently impair cognitive function in mice. Methods: TDF or nevirapine was orally administered to female BALB/c mice once a day for 8 weeks. On the 7th week of treatment, spatial learning and memory were assessed using the Morris water maze test. The levels of lipid peroxidation, BACE1, amyloid beta 1-42 (A beta 1-42) and A beta deposits were measured in the hippocampal tissue upon completion of treatment. Results: Chronic administration of nevirapine induced spatial learning and memory impairment in the Morris water maze test, whereas TDF did not have an effect. TDF and nevirapine administration increased hippocampal lipid peroxidation and A beta 1-42 concentration. Nevirapine further upregulated BACE1 expression and A beta deposits. Conclusion: Our results suggest that chronic exposure to TDF and nevirapine contributes to hippocampal lipid peroxidation and A beta accumulation, respectively, as well as spatial learning and memory deficits in mice even in the absence of HIV infection. These findings further support a possible link between ARV drug toxicity, A beta accumulation and the persistence of HANDs.