Endolysosome and autophagy dysfunction in Alzheimer disease

Abstract

Abnormalities of the neuronal endolysosome and macroautophagy/autophagy system are an early and prominent feature of Alzheimer disease (AD). <i>SORL1</i> is notable as a gene in which mutations are causal for a rare, autosomal dominant form of AD, and also variants that increase the risk of developing the common form of late-onset AD. In our recent study, we used patient-derived stem cells and CRISPR engineering to study the effects of <i>SORL1</i> mutations on the endolysosome and autophagy system in human forebrain neurons. <i>SORL1</i> mutations causal for monogenic AD are typically truncating mutations, and we found, using stem cells generated from an individual with dementia due to a heterozygous <i>SORL1</i> truncation mutation, that this class of mutation results in SORL1 haploinsufficiency. Reducing SORL1 protein by half results in disrupted endosomal trafficking in patient-derived neurons, which we confirmed by studying the endolysosomal system in isogenic CRISPR-engineered <i>SORL1</i> heterozygous null neurons. We also found that <i>SORL1</i> homozygous null neurons develop more severe phenotypes, with endosome abnormalities, lysosome dysfunction and defects in the degradative phase of autophagy. Endolysosome and autophagy defects in <i>SORL1</i> mutant neurons are dependent on <i>APP</i>, a key AD gene, as they are rescued by extracellular antisense oligonucleotides that reduce APP protein.