PT - JOURNAL ARTICLE AU - Anna L. Stern AU - Shivesh Ghura AU - Patrick J. Gannon AU - Cagla Akay-Espinoza AU - Jessica M. Phan AU - Alan C. Yee AU - Robert Vassar AU - Benjamin B. Gelman AU - Dennis L. Kolson AU - Kelly L. Jordan-Sciutto TI - BACE1 mediates HIV-associated and excitotoxic neuronal damage through an APP-dependent mechanism AID - 10.1523/JNEUROSCI.1280-17.2018 DP - 2018 Apr 09 TA - The Journal of Neuroscience PG - 1280-17 4099 - http://www.jneurosci.org/content/early/2018/04/09/JNEUROSCI.1280-17.2018.short 4100 - http://www.jneurosci.org/content/early/2018/04/09/JNEUROSCI.1280-17.2018.full AB - HIV-associated neurocognitive disorders (HAND) share common symptoms with Alzheimer's Disease (AD), which is characterized by amyloid-β (Aβ) plaques. Plaques are formed by aggregation of Aβ oligomers, which may be the toxic species in AD pathogenesis, and oligomers are generated by cleavage of amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 inhibitors reverse neuronal loss and cognitive decline in animal models of AD. Although studies have also found evidence of altered APP processing in HIV+ patients, it is unknown whether increased BACE1 expression or Aβ oligomer production is a common neuropathological feature of HAND. Moreover, it is unknown whether BACE1 or APP is involved in the excitotoxic, NMDA receptor-dependent component of HIV-associated neurotoxicity in vitro. Herein, we hypothesize that HIV-associated neurotoxicity is mediated by NMDAR-dependent elevation of BACE1 and subsequent altered processing of APP. Supporting this, we observed elevated levels of BACE1 and Aβ oligomers in CNS of male and female HIV+ patients. In a model of HIV-associated neurotoxicity in which rat neurons are treated with supernatants from HIV-infected human monocyte-derived macrophages (HIV/MDMs), we observed NMDAR-dependent elevation of BACE1 protein. NMDA treatment also increased BACE1, and both pharmacological BACE1 inhibition and genetic loss of APP were partially neuroprotective. Moreover, in APP-/- mouse neurons, NMDA-induced toxicity was BACE1-independent, indicating that cytotoxicity of BACE1 is dependent upon APP cleavage. Findings suggest that increased BACE1 and resultant Aβ oligomer production may contribute to HIV-associated neuropathogenesis, and inhibition of BACE1 could have therapeutic potential in HAND.SIGNIFICANCE STATEMENTHIV-associated neurocognitive disorders (HAND) represent a range of cognitive impairments affecting approximately 50% of HIV+ individuals. The specific causes of HAND are unknown, but evidence suggests that HIV-infected macrophage infiltration into the brain may cause neuronal damage. Herein, we show that neurons treated with conditioned media from HIV-infected macrophages have increased expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein implicated in Alzheimer's Disease (AD) pathogenesis. Moreover, inhibition of BACE1 prevented neuronal loss following conditioned media exposure, but had no effect on HIV-associated neurotoxicity in neurons lacking its cleavage target amyloid precursor protein (APP). We also observed increased BACE1 expression in HIV+ patient brain tissue, confirming the potential relevance of BACE1 as a therapeutic target in HAND.