. Cerebral Aβ deposition in an Aβ-precursor protein-transgenic 4 rhesus monkey. Elsevier: Aging Brain, June 10, 2022


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  1. The rhesus monkey can serve as model of sporadic/late onset AD based on some common phenotypes, such as age-associated accumulation of human sequence Aβ in plaques and cerebral amyloid angiopathy (CAA). Cognitive decline occurs with increasing age, and nonhuman primates are phylogenetically close to humans. However, several challenges exist in this model system, including the late age of onset of plaques (~20 years of age, 40 years being the typical maximum lifespan), and the relative lack of association between Aβ and cognitive deficits (Walker and Jucker, 2017; Peters et al., 1996; Sloane et al., 1997). Nonetheless, there is value in considering nonhuman primates as models of AD for preclinical research (Zeiss, 2020) given their responses to drugs and possible adverse effects being predictive of human responses.

    Here, Chan and colleagues describe a new APP transgenic nonhuman primate model in a conceptually fascinating proof-of-concept study with the goal of accelerating Aβ accumulation to earlier ages. Rhesus monkeys that overexpress the Swedish K670N/M671L and Indiana V717F mutations with a human polyubiquitin-C promotor (APPtg) were created. In the study, two wild-type rhesus monkeys were compared to two APPtg monkeys with longitudinal outcome measures including structural MRI, behavioral testing, and fluid biomarkers (plasma/CSF) and necropsy at 10 years of age. 

    In the APPtg animals, total brain volume and overall structure by MRI remained unchanged and not different from wild-type animals. CSF total tau was significantly higher in transgenic animals at 2 and 4 years of age compared to wild-type animals, but not at later ages. Interestingly, CSF Aβ1-42 was higher in the two transgenic animals at younger ages and declined with increasing age to reach levels observed in the wild-type animals. Decreasing levels of CSF Aβ are associated with increasing plaque accumulation in humans.

    At 6 years of age, the APPtg animals showed atypical behaviors on an emotional reactivity task along with more frequent stereotypies; at 9 years of age, they exhibited less preference for a novel image than the wild-type animals on an object in place memory task.

    At necropsy, Aβ pathology was present at 9 years of age in one of the two animals, almost 10 years early than that typically observed.  Notably, CAA was the most prominent feature of Aβ pathology (also thioflavin S-positive) and was detected in the occipital cortex (consistent with observations in human brain), but this contrasted with the lack of evidence of microbleeds by MRI. Scattered diffuse plaques and rare dense thioflavin-positive plaques had also formed, but most frequently in the occipital cortex.  Not surprisingly, since this is not a feature of most sporadic animal models of AD, no tauopathy was observed.  Little evidence of inflammation was detected.

    This is an elegant study. Even so, it is unclear if this novel approach of driving Aβ to earlier ages in nonhuman primates will be sufficient to improve the utility of the model at this time given that the phenotype (behavior, biomarkers, pathology) is modest.  Further, although this may reduce the number of animals that may be required for AD studies (unclear, however, given the variability in the two APPtg animals) it will not necessarily reduce the cost of preclinical research in this model system, which can be prohibitive.

    As the authors discuss, with older ages being examined in future studies, one could hypothesize that tau pathology may emerge. It would be fascinating to consider introducing tauopathy into the model, perhaps by inclusion of human tau or mutant versions of tau to determine if both pathologies are required to truly drive a cognitive phenotype that is more analogous to human dementia. Nonetheless, the CAA pathology observed here could suggest that APPtg nonhuman primates may be useful in the context of cerebrovascular neuropathology that is frequently observed in the AD brain.


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  2. Dr. Lary Walker and his team have taken an important step forward in demonstrating for the first time a transgenic (tg) rhesus monkey model of AD, where Aβ plaques and congophilic amyloid angiopathy (CAA) are accelerated by at least 10 years. One of two transgenic (tg) monkeys showed Aβ deposition approximately corresponding to Thal Phase I of AD and to stage 1 of Aβ-CAA. Both APP tg monkeys showed some behavioral abnormalities in comparison to non-tg controls.

    AD is uniquely human, with no model that matches all the features of the disease. This paper adds APP-tg rhesus monkeys to the list of AD models. They will be useful for preclinical testing of treatments for AD, in particular CAA. This model may have improved translatability over available mouse/rat transgenic models.

  3. This paper from Lary Walker and colleagues clearly represents a major effort. The great unknown with these monkey models is, what is the progression? What is the timeline? We can’t do the multiple time points like we would in a mouse model. Would the authors have seen more pathology at 20 years old? Maybe, but that experiment would be very hard to do. As it is, they waited 10 years, which deserves a lot of credit.

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