Endolysosome and autophagy dysfunction in Alzheimer disease

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Endolysosome and autophagy system abnormalities are early features of Alzheimer disease (AD).
• SORL1 gene mutations are linked to both rare autosomal dominant and common late-onset AD.
• SORL1 plays a critical role in neuronal function and its dysfunction is implicated in AD pathogenesis.

Purpose of the Study:

• To investigate the impact of SORL1 mutations on the endolysosome and autophagy system in human forebrain neurons.
• To elucidate the cellular mechanisms by which SORL1 dysfunction contributes to Alzheimer disease.
• To explore the relationship between SORL1, APP, and neuronal dysfunction in AD.

Main Methods:

• Utilized patient-derived stem cells from individuals with SORL1 mutations.
• Employed CRISPR engineering to create isogenic SORL1 heterozygous and homozygous null neuronal models.
• Analyzed endolysosome trafficking, lysosome function, and autophagy in vitro.
• Investigated the role of APP by using antisense oligonucleotides to reduce APP protein levels.

Main Results:

• Heterozygous SORL1 truncation mutations lead to SORL1 haploinsufficiency and disrupted endosomal trafficking in patient-derived neurons.
• CRISPR-engineered SORL1 heterozygous null neurons confirmed endosomal trafficking defects.
• SORL1 homozygous null neurons exhibited more severe phenotypes, including endosome abnormalities, lysosome dysfunction, and impaired autophagy.
• Endolysosome and autophagy defects in SORL1 mutant neurons were dependent on APP and rescued by reducing APP levels.

Conclusions:

• SORL1 haploinsufficiency due to truncation mutations disrupts neuronal endolysosome and autophagy pathways, contributing to Alzheimer disease.
• Complete loss of SORL1 function exacerbates these cellular defects, highlighting its critical role in neuronal homeostasis.
• APP protein levels are crucial modulators of SORL1-associated endolysosome and autophagy dysfunction in Alzheimer disease.