Document Type
Article
Publication Date
5-1-2024
Original Citation
Homanics G,
Park J,
Bailey L,
Schaeffer D,
Schaeffer L,
He J,
Li S,
Zhang T,
Haber A,
Spruce C,
Greenwood A,
Murai T,
Schultz L,
Mongeau L,
Ha S,
Oluoch J,
Stein B,
Choi S,
Huhe H,
Thathiah A,
Strick P,
Carter GW,
Silva A,
Sukoff Rizzo S.
Early molecular events of autosomal-dominant Alzheimer's disease in marmosets with PSEN1 mutations. Alzheimers Dement. 2024;20(5):3455-71.
Keywords
JMG, Animals, Presenilin-1, Alzheimer Disease, Callithrix, Male, Female, Brain, Amyloid beta-Peptides, Disease Models, Animal, Point Mutation, Animals, Genetically Modified, CRISPR-Cas Systems, Gene Knock-In Techniques, Mutation, Humans
JAX Source
Alzheimers Dement. 2024;20(5):3455-71.
ISSN
1552-5279
PMID
38574388
DOI
https://doi.org/10.1002/alz.13806
Grant
National Institutes of Health; NIA, Grant/Award Number: U19AG074866; University of Pittsburgh Medical Center, Grant/Award Number: IPA 2019 No. 16
Abstract
INTRODUCTION: Fundamental questions remain about the key mechanisms that initiate Alzheimer's disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically engineered marmosets that carry knock-in (KI) point mutations in the presenilin 1 (PSEN1) gene that can be studied from birth throughout lifespan.
METHODS: CRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non-invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures.
RESULTS: Prior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non-carriers. Analysis of brain revealed alterations in several enzyme-substrate interactions within the gamma secretase complex prior to adulthood.
DISCUSSION: Marmosets carrying KI point mutations in PSEN1 provide the opportunity to study the earliest primate-specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression.
HIGHLIGHTS: We report the successful generation of genetically engineered marmosets harboring knock-in point mutations in the PSEN1 gene. PSEN1 marmosets and their germline offspring recapitulate the early emergence of AD-related biomarkers. Studies as early in life as possible in PSEN1 marmosets will enable the identification of primate-specific mechanisms that drive disease progression.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.