Activation of TRPML1 clears intraneuronal Aβ in preclinical models of HIV infection

Mihyun Bae, Neha Patel, Haoxing Xu, Mingwaoh Lee, Kumiko Tominaga-Yamanaka, Avindra Nath, Jonathan Geiger, Myriam Gorospe, Mark P. Mattson, Norman J. Haughey

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Antiretroviral therapy extends the lifespan of human immunodeficiency virus (HIV)-infected patients, but many survivors develop premature impairments in cognition. These residual cognitive impairments may involve aberrant deposition of amyloid β-peptides (Aβ). By unknown mechanisms, Aβ accumulates in the lysosomal and autophagic compartments of neurons in the HIV-infected brain. Here we identify the molecular events evoked by the HIV coat protein gp120 that facilitate the intraneuronal accumulation of Aβ. We created a triple transgenic gp120/APP/PS1 mouse that recapitulates intraneuronal deposition of Aβ in a manner reminiscent of the HIV-infected brain. In cultured neurons, we found that the HIV coat protein gp120 increased the transcriptional expression of BACE1 through repression of PPARγ, and increased APP expression by promoting interaction of the translation-activating RBP heterogeneous nuclear ribonucleoprotein C with APP mRNA. APP and BACE1 were colocalized into stabilized membrane microdomains, where the β-cleavage of APP and Aβ formation were enhanced. Aβ-peptides became localized to lysosomes that were engorged with sphingomyelin and calcium. Stimulating calcium efflux from lysosomes with a TRPM1 agonist promoted calcium efflux, luminal acidification, and cleared both sphingomyelin and Aβ from lysosomes. These findings suggest that therapeutics targeted to reduce lysosomal pH in neurodegenerative conditions may protect neurons by facilitating the clearance of accumulated sphingolipids and Aβ-peptides.

Original languageEnglish (US)
Pages (from-to)11485-11503
Number of pages19
JournalJournal of Neuroscience
Volume34
Issue number34
DOIs
StatePublished - Aug 20 2014

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Keywords

  • Amyloid
  • Dementia
  • Endosome
  • HIV
  • Lysosome
  • Neuron

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Bae, M., Patel, N., Xu, H., Lee, M., Tominaga-Yamanaka, K., Nath, A., Geiger, J., Gorospe, M., Mattson, M. P., & Haughey, N. J. (2014). Activation of TRPML1 clears intraneuronal Aβ in preclinical models of HIV infection. Journal of Neuroscience, 34(34), 11485-11503. https://doi.org/10.1523/JNEUROSCI.0210-14.2014