Generation of Transgenic Cynomolgus Monkeys Overexpressing the Gene for Amyloid-β Precursor Protein

Abstract

Alzheimer's disease (AD) is the most common cause of dementia and understanding its pathogenesis should lead to improved therapeutic and diagnostic methods. Although several groups have developed transgenic mouse models overexpressing the human amyloid-␤ precursor protein (APP) gene with AD mutations, with and without presenilin mutations, as well as APP gene knock-in mouse models, these animals display amyloid pathology but do not show neurofibrillary tangles or neuronal loss. This presumably is due to differences between the etiology of the aged-related human disease and the mouse models. Here we report the generation of two transgenic cynomolgus monkeys overexpressing the human gene for APP with Swedish, Artic, and Iberian mutations, and demonstrated expression of gene tagged green fluorescent protein marker in the placenta, amnion, hair follicles, and peripheral blood. We believe that these nonhuman primate models will be very useful to study the pathogenesis of dementia and AD. However, generated Tg monkeys still have some limitations. We employed the CAG promoter, which will promote gene expression in a non-tissue specific manner. Moreover, we used transgenic models but not knock-in models. Thus, the inserted transgene destroys endogenous gene(s) and may affect the phenotype(s). Nevertheless, it will be of great interest to determine whether these Tg monkeys will develop tauopathy and neurodegeneration similar to human AD.

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

“…Structural LC imaging in these toxicity models combined with post-mortem stereology could help disentangle the different sources of contrast, including the contributions of neuromelanin which is not possible in rodents. Development of transgenic non-human primates is also ongoing, and could be especially important for understanding genetic contributions to progression of endogenous neuropathology within the LC across aging and disease ( Arnsten et al, 2019 ; Seita et al, 2020 ). Studies should also incorporate other imaging modalities in non-human primate models to better understand the effects of these manipulations on LC axon health and connectivity.…”

Deconstructing Alzheimer’s Disease: How to Bridge the Gap between Experimental Models and the Human Pathology?

“…A breakthrough would be the generation of transgenic AD NHPs. In particular, the grey mouse lemur would be suitable for transgenesis due to its small size, shorter lifespan, and its ability to spontaneously develop an AD-like pathology [89,242].…”

“…This process could enrich the colony of AD-affected animals. Alternatively, a solution could be the enrichment of colonies with progenies of the most affected individuals or the development of genetic tools to study transgenic animals with fAD mutations [89,242].…”

Emerging Electroencephalographic Biomarkers to Improve Preclinical to Clinical Translation in Alzheimer’s Disease

“…It has been demonstrated that aggregation of Aβ plaques which is similar in sequence to humans were naturally found in aged animals accompanied by declining cognitive function ( Geula et al, 2002 ; Sani et al, 2003 ; Oikawa et al, 2010 ). In NHPs, some AD models have already been published including rhesus monkeys, cynomolgus monkeys, vervet monkeys, and marmosets ( Geula et al, 1998 , 2002 ; Lemere et al, 2004 ; Forny-Germano et al, 2014 ; Yang et al, 2014 ; Melamed et al, 2017 ; Seita et al, 2020 ). Details of each model were described elsewhere but it is noteworthy that recent technological advances have made it possible to generate genetically engineered animal models in NHPs ( Sasaki et al, 2009 ; De Felice and Munoz, 2016 ; Li et al, 2019 ; Seita et al, 2020 ).…”