BACE1 mediates HIV-associated and excitotoxic neuronal damage through an APP-dependent mechanism

Anna L. Stern, Shivesh Ghura, Patrick J. Gannon, Cagla Akay-Espinoza, Jessica M. Phan, Alan C. Yee, Robert Vassar, Benjamin Gelman, Dennis L. Kolson, Kelly L. Jordan-Sciutto

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Abstract

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 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, 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.

Original languageEnglish (US)
Pages (from-to)4288-4300
Number of pages13
JournalJournal of Neuroscience
Volume38
Issue number18
DOIs
StatePublished - May 2 2018

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Amyloid beta-Protein Precursor
HIV-1
Enzymes
HIV
Alzheimer Disease
N-Methylaspartate
Neurons

Keywords

  • Alzheimer’s disease
  • APP
  • BACE1
  • Excitotoxicity
  • HIV-associated neurocognitive disorders
  • NMDA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Stern, A. L., Ghura, S., Gannon, P. J., Akay-Espinoza, C., Phan, J. M., Yee, A. C., ... Jordan-Sciutto, K. L. (2018). BACE1 mediates HIV-associated and excitotoxic neuronal damage through an APP-dependent mechanism. Journal of Neuroscience, 38(18), 4288-4300. https://doi.org/10.1523/JNEUROSCI.1280-17.2018

BACE1 mediates HIV-associated and excitotoxic neuronal damage through an APP-dependent mechanism. / Stern, Anna L.; Ghura, Shivesh; Gannon, Patrick J.; Akay-Espinoza, Cagla; Phan, Jessica M.; Yee, Alan C.; Vassar, Robert; Gelman, Benjamin; Kolson, Dennis L.; Jordan-Sciutto, Kelly L.

In: Journal of Neuroscience, Vol. 38, No. 18, 02.05.2018, p. 4288-4300.

Research output: Contribution to journalArticle

Stern, AL, Ghura, S, Gannon, PJ, Akay-Espinoza, C, Phan, JM, Yee, AC, Vassar, R, Gelman, B, Kolson, DL & Jordan-Sciutto, KL 2018, 'BACE1 mediates HIV-associated and excitotoxic neuronal damage through an APP-dependent mechanism', Journal of Neuroscience, vol. 38, no. 18, pp. 4288-4300. https://doi.org/10.1523/JNEUROSCI.1280-17.2018
Stern, Anna L. ; Ghura, Shivesh ; Gannon, Patrick J. ; Akay-Espinoza, Cagla ; Phan, Jessica M. ; Yee, Alan C. ; Vassar, Robert ; Gelman, Benjamin ; Kolson, Dennis L. ; Jordan-Sciutto, Kelly L. / BACE1 mediates HIV-associated and excitotoxic neuronal damage through an APP-dependent mechanism. In: Journal of Neuroscience. 2018 ; Vol. 38, No. 18. pp. 4288-4300.
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