A new study implicates a role for BACE1 in HIV-associated neurocognitive disorders (HANDs). BACE1 is a protein involved in the pathogenesis of Alzheimer’s disease (AD). An increase in BACE1 with resultant production of amyloid-β (Aβ) may contribute to HIV-associated neuropathogenesis, found Anna J. Stern, PhD, University of Pennsylvania, Philadelphia, PA, and colleagues. Further, inhibition of BACE1 may prevent neuronal loss, and may therefore have therapeutic potential in HANDs. Their research appears in the Journal of Neuroscience.
“These data add to a growing body of evidence that there are overlapping neuropathological mechanisms in AD and HAND,” the researchers wrote. “Aβ oligomers are thought to be the toxic species promoting neuropathogenesis in AD, and our data indicate that they may play a similar role in HAND. BACE1 is increased in post mortem brains of AD patients, and in animal models of AD BACE1 inhibitors reverse neuronal loss and cognitive deficits. To our knowledge, our study provides the first evidence that BACE1 is similarly altered in HIV-positive patient brains and that exposure to cultured media from HIV-infected monocyte-derived macrophages [MDMs] can increase BACE1 levels in neurons.”
Dr. Stern and colleagues found an elevation of Aβ oligomers in the hippocampus of HIV-positive individuals and an increase of BACE1 in the frontal cortex of HIV-positive individuals compared with uninfected controls. This latter finding was replicated in the frontal cortex of a second independent cohort of 20 HIV-negative and 40 HIV-positive individuals, 20 of whom had HAND.
BACE1 has also been previously found to be increased by antiretroviral (ART) drugs from at least two classes, which suggests that HIV-positive patients treated with ART therapy may undergo additive increases in BACE1 due to viral infection as well as therapeutic intervention.
BACE1 was found to be increased in primary neurons treated with supernatants from HIV-infected human MDMs. In primary rat neurons, this increase was found to dependent on NMDA receptor (NMDAR) signaling, as a significant dose-dependent increase in BACE1 protein levels in rat primary neurons was observed following 16 hours of treatment with NMDA alone.
The NMDAR activation shifted amyloid precursor protein (APP) processing toward the amyloidogenic pathway. Neurotoxicity induced by NMDA or HIV/MDM supernatants could be attenuated by pretreatment with a BACE1 inhibitor.
In APP knock-out mouse neurons, the critical function of BACE1 responsible for its role in NMDA-induced neurotoxicity was found to be dependent on the expression of APP, indicating that APP cleavage is the relevant BACE1 function responsible for toxicity.
“Moreover, by identifying NMDAR signaling and altered APP processing as critical factors that mediate the role of BACE1 in HIV-associated neurotoxicity, we provide support for the potential efficacy of several avenues for therapeutic intervention in HAND in addition to direct pharmacological targeting of BACE1,” concluded Dr. Stern and fellow researchers.