In vivoevidence thatSORL1, encoding the endosomal recycling receptor SORLA, can function as a causal gene in Alzheimer’s Disease

Abstract

The few established causal genes in Alzheimer's disease (AD), mutations in APP and PSENs, have been functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. SORL1, a gene encoding the endosome recycling receptor SORLA, epidemiologically behaves as a causal gene when truncating mutations lead to partial loss of protein function. Here, in an effort to test whether SORL1 can indeed function as an AD causal gene, we used CRISPR-Cas9-based gene editing to develop a novel model of SORL1 haploinsufficiency in Goettingen Minipigs taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young minipigs was found to phenocopy the preclinical in vivo profile of AD observed with other causal genes, resulting in spinal fluid abnormalities in Aβ and tau, with no evident neurodegeneration or amyloid plaque formation. These studies provide functional support that SORL1 is a bona fide causal gene in AD, and when taken together with recent insight on other AD-causal genes, support the idea that dysfunctional endosomal recycling is a dominant pathogenic pathway in the disease.

Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling

“…Recent genetic studies have established that SORL1 -truncating mutations confer an extremely high AD risk, on par with the extreme high risk conferred by mutations in the amyloid precursor proteins (APP) and the presenilins (PSENs) ( Holstege et al, 2017 ; Scheltens et al, 2021 ). Complementary functional studies have shown that SORL1 depletion and causal APP/PSEN mutations appear to phenocopy each other by inducing in neurons endosomal traffic jams ( Knupp et al, 2020 ; Kwart et al, 2019 ), APP misprocessing, and accelerated Aβ and tau secretion ( Maia et al, 2013 ; Andersen et al, 2021 ).…”