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

Abstract

Objectives: Growing evidence suggested that antiretroviral drugs (ARV) may promote β-amyloid accumulation in HIV‐1‐infected brain and the persistence of HIV-associated neurocognitive disorders (HAND). It has also been shown that lipid peroxidation upregulates β-site APP-cleaving enzyme 1 (BACE1) expression and subsequent promote β-amyloid peptide production. In the present study, we examined whether chronic exposure to the anti-HIV drugs tenofovir disoproxil fumarate and nevirapine induces lipid peroxidation thereby promoting BACE1 and β-amyloid generation and consequently impair cognitive function in mice. Methods: Tenofovir disoproxil fumarate or nevirapine were 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, β-site APP cleaving enzyme 1 (BACE1), β-amyloid 1-42 and β-amyloid (Aβ) 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 tenofovir disoproxil fumarate did not have an effect. Tenofovir disoproxil fumarate and nevirapine administration increased hippocampal lipid peroxidation and β-amyloid 1-42 concentration. Nevirapine further upregulated BACE1 expression and β-amyloid (Aβ) deposits. Conclusion: Our results suggest that chronic exposure to tenofovir disoproxil fumarate and nevirapine contributes to hippocampal lipid peroxidation and β-amyloid accumulation, respectively, as well as spatial learning and memory deficits in mice even in the absence HIV-infection. These findings further support a possible link between antiretroviral drug toxicity, β-amyloid accumulation and the persistence of HIV associated neurocognitive disorders.

Higher Cerebrospinal Fluid Biomarkers of Neuronal Injury in Hiv-Associated Neurocognitive Impairment

“…Thus, combination ARV treatment of SweAPP N2a cells increased Aβ generation and markedly inhibited microglial phagocytosis of FITC-Aβ1-42 peptides in murine microglia (Giunta et al 2011). In another study, chronic exposure to tenofovir, a component of most current regimens contributed to Aβ accumulation as well as spatial learning and memory deficits in mice (Zulu et al 2020).…”

The integrated stress response signaling during the persistent HIV infection

“… 30 In mice, the NNRTI nevirapine was associated with cognitive impairment and brain lipid peroxidation. 31 …”

Effects of antiretroviral treatment on central and peripheral immune response in mice with EcoHIV infection

“…However, preclinical models point to ART-induced dysregulation of peripheral and central nervous system immune function (Zulu et al, 2021). Cognitive outcomes include spatial learning and memory impairments following treatment with nevirapine (Zulu et al, 2020) or emtricitabine + tenofovir disoproxil fumarate (Zulu et al, 2021) in the absence of infection. Thus, preclinical research will be essential to fully characterize the independent and interactive effects of ART on neural and immune outcomes.…”