Acidifying Endolysosomes Prevented Low-Density Lipoprotein-Induced Amyloidogenesis

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Cholesterol dyshomeostasis is implicated in sporadic Alzheimer's disease (AD) pathogenesis.
• Low-density lipoprotein (LDL) entry into the brain and endolysosome de-acidification are linked to amyloidogenesis.
• The precise role of endolysosome pH in LDL-induced amyloid-beta (Aβ) generation requires further elucidation.

Purpose of the Study:

• To test the hypothesis that endolysosome de-acidification is central to Aβ generation.
• To investigate if acidifying endolysosomes protects against LDL-induced increases in Aβ levels in neurons.

Main Methods:

• Demonstrated LDL's effect on endolysosome pH and Aβ levels in neurons.
• Utilized ML-SA1, a TRPML1 channel agonist, to induce endolysosome acidification.
• Assessed the impact of TRPML1 knockdown on ML-SA1 and LDL effects.
• Quantified Aβ and BACE1 levels within endolysosomes and measured BACE1 activity.

Main Results:

• LDL, unlike HDL, de-acidified endolysosomes and increased intraneuronal and secreted Aβ.
• ML-SA1 acidified endolysosomes, blocking LDL-induced Aβ increases and BACE1 accumulation/activity.
• TRPML1 knockdown attenuated ML-SA1's effect and exacerbated LDL-induced Aβ increases.
• LDL downregulated TRPML1 protein levels.

Conclusions:

• Endolysosome de-acidification is implicated in LDL-induced Aβ generation.
• Activating TRPML1 channels to acidify endolysosomes may offer a protective strategy against sporadic AD.
• Targeting endolysosome pH presents a potential therapeutic avenue for Alzheimer's disease.