Acidifying Endolysosomes Prevented Low-Density Lipoprotein-Induced Amyloidogenesis

J Alzheimers Dis. 2019;67(1):393-410. doi: 10.3233/JAD-180941.

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.

Keywords: Amyloid-β; BACE1; ML-SA1; TRPML1; cholesterol; endolysosome pH; low-density lipoprotein; neurons.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acids
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / biosynthesis*
  • Animals
  • Aspartic Acid Endopeptidases / metabolism
  • Gene Knockdown Techniques
  • Lipoproteins, HDL / pharmacology
  • Lipoproteins, LDL / pharmacology*
  • Lysosomes / chemistry*
  • Phthalimides / pharmacology
  • Primary Cell Culture
  • Quinolines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Transient Receptor Potential Channels / agonists
  • Transient Receptor Potential Channels / genetics
  • Transient Receptor Potential Channels / metabolism

Substances

  • Acids
  • Amyloid beta-Peptides
  • Lipoproteins, HDL
  • Lipoproteins, LDL
  • ML-SA1 compound
  • Mcoln1 protein, rat
  • Phthalimides
  • Quinolines
  • Transient Receptor Potential Channels
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, rat