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.
If you do not see content above, kindly GO TO SOURCE.
Not all publishers encode content in a way that enables republishing at Neuro.vip.
This post is Copyright: Gregg E. Homanics,
Jung Eun Park,
Lauren Bailey,
David J. Schaeffer,
Lauren Schaeffer,
Jie He,
Shuoran Li,
Tingting Zhang,
Annat Haber,
Catrina Spruce,
Anna Greenwood,
Takeshi Murai,
Laura Schultz,
Lauren Mongeau,
Seung‐Kwon Ha,
Julia Oluoch,
Brianne Stein,
Sang Ho Choi,
Hasi Huhe,
Amantha Thathiah,
Peter L. Strick,
Gregory W. Carter,
Afonso C. Silva,
Stacey J. Sukoff Rizzo | April 5, 2024