Acidifying Endolysosomes Prevented Low-Density Lipoprotein-Induced Amyloidogenesis

Liang Hui, Mahmoud L. Soliman, Nicholas H. Geiger, Nicole M. Miller, Zahra Afghah, Koffi L. Lakpa, Xuesong Chen, Jonathan D. Geiger

Research output: Contribution to journalReview article

4 Scopus citations

Abstract

Cholesterol dyshomeostasis has been linked to the pathogenesis of sporadic Alzheimer's disease (AD). In furthering the understanding of mechanisms by which increased levels of circulating cholesterol augments the risk of developing sporadic AD, others and we have reported that low-density lipoprotein (LDL) enters brain parenchyma by disrupting the blood-brain barrier and that endolysosome de-acidification plays a role in LDL-induced amyloidogenesis in neurons. Here, we tested the hypothesis that endolysosome de-acidification was central to amyloid-β (Aβ) generation and that acidifying endolysosomes protects against LDL-induced increases in Aβ levels in neurons. We demonstrated that LDL, but not HDL, de-acidified endolysosomes and increased intraneuronal and secreted levels of Aβ. ML-SA1, an agonist of endolysosome-resident TRPML1 channels, acidified endolysosomes, and TRPML1 knockdown attenuated ML-SA1-induced endolysosome acidification. ML-SA1 blocked LDL-induced increases in intraneuronal and secreted levels of Aβ as well as Aβ accumulation in endolysosomes, prevented BACE1 accumulation in endolysosomes, and decreased BACE1 activity levels. LDL downregulated TRPML1 protein levels, and TRPML1 knockdown worsens LDL-induced increases in Aβ. Our findings suggest that endolysosome acidification by activating TRPML1 may represent a protective strategy against sporadic AD.

Original languageEnglish (US)
Pages (from-to)393-410
Number of pages18
JournalJournal of Alzheimer's Disease
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2019

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Keywords

  • Amyloid-β
  • BACE1
  • ML-SA1
  • TRPML1
  • cholesterol
  • endolysosome pH
  • low-density lipoprotein
  • neurons

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Hui, L., Soliman, M. L., Geiger, N. H., Miller, N. M., Afghah, Z., Lakpa, K. L., Chen, X., & Geiger, J. D. (2019). Acidifying Endolysosomes Prevented Low-Density Lipoprotein-Induced Amyloidogenesis. Journal of Alzheimer's Disease, 67(1), 393-410. https://doi.org/10.3233/JAD-180941