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A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency.

ABSTRACT: The established causal genes in Alzheimer's disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%-3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD.

SUBMITTER: Andersen OM

PROVIDER: S-EPMC9512670 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency.

Andersen Olav M OM Bøgh Nikolaj N Landau Anne M AM Pløen Gro G GG Jensen Anne Mette G AMG Monti Giulia G Ulhøi Benedicte P BP Nyengaard Jens R JR Jacobsen Kirsten R KR Jørgensen Margarita M MM Holm Ida E IE Kristensen Marianne L ML Alstrup Aage Kristian O AKO Hansen Esben S S ESS Teunissen Charlotte E CE Breidenbach Laura L Droescher Mathias M Liu Ying Y Pedersen Hanne S HS Callesen Henrik H Luo Yonglun Y Bolund Lars L Brooks David J DJ Laustsen Christoffer C Small Scott A SA Mikkelsen Lars F LF Sørensen Charlotte B CB

Cell reports. Medicine 20220912 9

The established causal genes in Alzheimer's disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%-3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a ...[more]

PMID: 36099918

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Project description:IntroductionThe SORL1 locus exhibits protective effects against Alzheimer's disease (AD) across ancestries, yet systematic studies in diverse populations are sparse.MethodsLogistic regression identified AD-associated SORL1 haplotypes in East Asian (N = 5249) and European (N = 8588) populations. Association analysis between SORL1 haplotypes and AD-associated traits or plasma biomarkers was conducted. The effects of non-synonymous mutations were assessed in cell-based systems.ResultsProtective SORL1 variants/haplotypes were identified in the East Asian and European populations. Haplotype Hap_A showed a strong protective effect against AD in East Asians, linked to less severe AD phenotypes, higher SORL1 transcript levels, and plasma proteomic changes. A missense variant within Hap_A, rs2282647-C allele, was linked to a lower risk of AD and decreased expression of a truncated SORL1 protein isoform.DiscussionOur transethnic analysis revealed key SORL1 haplotypes that exert protective effects against AD, suggesting mechanisms of the protective role of SORL1 in AD.HighlightsWe examined the AD-protective mechanisms of SORL1 in the general population across diverse ancestral backgrounds by jointly analyzing data from three East Asian cohorts (ie, mainland China, Hong Kong, and Japan) and a European cohort. Comparative analysis unveiled key ethnic-specific SORL1 genetic variants and haplotypes. Among these, the SORL1 minor haplotype, Hap_A, emerged as the primary AD-protective factor in East Asians. Hap_A exerts significant AD-protective effects in both APOE ε4 carriers and non-carriers. SORL1 haplotype Hap_A is associated with cognitive function, brain volume, and the activity of specific neuronal and immune-related pathways closely connected to AD risk. Protective variants within Hap_A are linked to increased SORL1 expression in human tissues. We identified an isoform-specific missense variant in Hap_A that modifies the function and levels of a truncated SORL1 protein isoform that is poorly investigated.

Dataset Information

A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency.

Publications

A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency.

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