title: Activation of TRPML1 clears intraneuronal Aβ in preclinical models of HIV infection.
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.
authors.affiliation: Johns Hopkins University School of Medicine, Department of Neurology, Division of Neuroimmunology and Neurological Infections, Baltimore, Maryland 21287.
authors.forename: Mihyun
authors.initials: M
authors.lastname: Bae
authors.affiliation: Johns Hopkins University School of Medicine, Department of Neurology, Division of Neuroimmunology and Neurological Infections, Baltimore, Maryland 21287.
authors.forename: Neha
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Haoxing
authors.initials: H
authors.lastname: Xu
authors.affiliation: Section of Infections of the Nervous Systems, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Mingwaoh
authors.initials: M
authors.lastname: Lee
authors.affiliation: Laboratories of Genetics and.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tominaga-Yamanaka
authors.affiliation: Section of Infections of the Nervous Systems, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota 58202-9037, and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Geiger
authors.affiliation: Laboratories of Genetics and.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.affiliation: Neurosciences, National Institute on Aging-IRP, National Institutes of Health, Baltimore, Maryland 21224-6825.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Johns Hopkins University School of Medicine, Department of Neurology, Division of Neuroimmunology and Neurological Infections, Baltimore, Maryland 21287, nhaughe1@jhmi.edu.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Haughey
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology* / Q000821:virology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000494:pharmacology; D015658:HIV Infections / Q000473:pathology*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; C416674:MCOLN1 protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D050051:Transient Receptor Potential Channels; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: HIV; amyloid; dementia; endosome; lysosome; neuron