A non-human primate model of familial Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a major cause of dementia, with the number of patients with this condition anticipated to exceed 50 million worldwide in the near future. Despite extensive research efforts, no effective measures are available to facilitate the prevention or treatment of AD, which is due in part to a lack of animal models able to closely replicate a human-like disease state. Here, we describe the generation of three mutant marmoset individuals in which exon 9 of PSEN1 gene product has been deleted (PSEN1-DeltaE9). Such DeltaE9 mutations have been reported to cause early on-set familial AD (references 1-5). We used Transcription Activator-Like Effector Nuclease (TALEN) to destroy the 3' splice site of exon 9 in the marmoset PSEN1 gene. To this end, TALEN exhibits high genome-editing efficacy, generates few off-target effects, and produces minimal mosaicism. Indeed, whole genome sequencing and other analyses illustrated an absence of off-target effects and an apparent absence of mosaicism. Fibroblasts obtained from newborn marmosets exhibited uncleaved full-length presenilin 1 protein (PS1) caused by the perturbation of PS1 endoproteolysis as well as an increased ratio of Abeta42/Abeta40 production, a signature of familial AD pathogenesis. To our knowledge, this is the first non-human primate model of familial AD. We intend to make our marmoset model available to the research community to facilitate the global fight against AD.

Diffusion MRI Anisotropy in the Cerebral Cortex is Determined by Unmyelinated Tissue Features

“…Changes in mean diffusivity in gray matter have been associated with Alzheimer's pathology 64 . The present findings may inform the development of dMRI models of the gray matter, perhaps to specifically target neuroinflammation 9 or other aspects of Alzheimer's pathology in the earliest stages 65 .…”

A Review of the Current Mammalian Models of Alzheimer’s Disease and Challenges That Need to Be Overcome

“…Nonetheless, it is a promising development. Around the same time, a KI marmoset model of AD was reported in bioRxiv, carrying the PSEN1 delta E9 mutation [ 219 ]. The ratio of Aβ 1 – 42 to Aβ 1 – 40 production in fibroblasts was double that of the controls in the juvenile monkeys, indicating an early pathological change.…”

Visual Neuroscience Methods for Marmosets: Efficient Receptive Field Mapping and Head-Free Eye Tracking

“…Recently, there have been successes in creating transgenic marmosets as disease models ( Sasaki et al, 2009 ; Tomioka et al, 2017a , b ; Sato et al, 2020 ) and in the use of genetically encoded calcium indicators ( Park et al, 2016 ). Because of the relatively high reproduction rates and the fact that marmosets often give birth to twins, it is likely that the marmoset will become a viable transgenic primate model ( Shen, 2013 ; Kishi et al, 2014 ; Mitchell and Leopold, 2015 ).…”