BACE1 Mediates HIV-Associated and Excitotoxic Neuronal Damage Through an APP-Dependent Mechanism.

TitleBACE1 Mediates HIV-Associated and Excitotoxic Neuronal Damage Through an APP-Dependent Mechanism.
Publication TypeJournal Article
Year of Publication2018
AuthorsStern, AL, Ghura, S, Gannon, PJ, Akay-Espinoza, C, Phan, JM, Yee, AC, Vassar, R, Gelman, BB, Kolson, DL, Jordan-Sciutto, KL
JournalJ Neurosci
Date Published2018 05 02
KeywordsAdult, AIDS Dementia Complex, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Enzyme Inhibitors, Excitatory Amino Acid Agonists, Female, Hippocampus, HIV Infections, Humans, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, N-Methylaspartate, Neurons, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate

HIV-associated neurocognitive disorders (HANDs) 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, NMDAR-dependent component of HIV-associated neurotoxicity 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, 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 knock-out (APP) mouse neurons, NMDA-induced toxicity was BACE1 independent, indicating that cytotoxicity of BACE1 is dependent upon APP cleavage. Our findings suggest that increased BACE1 and the resultant Aβ oligomer production may contribute to HIV-associated neuropathogenesis and inhibition of BACE1 could have therapeutic potential in HANDs. HIV-associated neurocognitive disorders (HANDs) represent a range of cognitive impairments affecting ∼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 pathogenesis. Moreover, inhibition of BACE1 prevented neuronal loss after conditioned media exposure, but had no effect on HIV-associated neurotoxicity in neurons lacking its cleavage target amyloid precursor protein. We also observed increased BACE1 expression in HIV patient brain tissue, confirming the potential relevance of BACE1 as a therapeutic target in HANDs.

Alternate JournalJ Neurosci
PubMed ID29632166
PubMed Central IDPMC5932640
Grant ListR01 MH106967 / MH / NIMH NIH HHS / United States
R01 MH098742 / MH / NIMH NIH HHS / United States
R01 MH104134 / MH / NIMH NIH HHS / United States
R01 MH109382 / MH / NIMH NIH HHS / United States
U24 MH100930 / MH / NIMH NIH HHS / United States
R01 MH111389 / MH / NIMH NIH HHS / United States