| First Author | Bae M | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 34 | Pages | 11485-503 |
| PubMed ID | 25143627 | Mgi Jnum | J:216162 |
| Mgi Id | MGI:5607818 | Doi | 10.1523/JNEUROSCI.0210-14.2014 |
| Citation | Bae M, et al. (2014) Activation of TRPML1 clears intraneuronal Abeta in preclinical models of HIV infection. J Neurosci 34(34):11485-503 |
| abstractText | 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 beta-peptides (Abeta). By unknown mechanisms, Abeta 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 Abeta. We created a triple transgenic gp120/APP/PS1 mouse that recapitulates intraneuronal deposition of Abeta 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 PPARgamma, 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 beta-cleavage of APP and Abeta formation were enhanced. Abeta-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 Abeta 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 Abeta-peptides. |
