Bridging the rodent to human translational gap: Marmosets as model systems for the study of Alzheimer's disease

Abstract

IntroductionOur limited understanding of the mechanisms that trigger the emergence of Alzheimer's disease (AD) has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We believe that the development of a non‐human primate model of AD will be an essential step toward overcoming limitations of other model systems and is crucial for investigating primate‐specific mechanisms underlying the cellular and molecular root causes of the pathogenesis and progression of AD.MethodsA new consortium has been established with funding support from the National Institute on Aging aimed at the generation, characterization, and validation of Marmosets As Research Models of AD (MARMO‐AD). This consortium will study gene‐edited marmoset models carrying genetic risk for AD and wild‐type genetically diverse aging marmosets from birth throughout their lifespan, using non‐invasive longitudinal assessments. These include characterizing the genetic, molecular, functional, behavioral, cognitive, and pathological features of aging and AD.ResultsThe consortium successfully generated viable founders carrying PSEN1 mutations in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community.DiscussionBy establishing marmoset models of AD, we will be able to investigate primate‐specific cellular and molecular root causes that underlie the pathogenesis and progression of AD, overcome limitations of other model organisms, and support future translational studies to accelerate the pace of bringing therapies to patients.

Early molecular events of autosomal‐dominant Alzheimer's disease in marmosets with PSEN1 mutations

“…The elevated levels of Aβ42 and Aβ42:40 in plasma from adolescence aligns with the early emergence of AD biomarkers reported in children carrying PSEN1 mutations 15–17 . Importantly, this phenotype is conserved in the germline offspring of the founders, which are the subjects most pertinent for these and future studies 21 …”

“…The present results provide evidence that the PSEN1 mutations engineered in the marmosets create AD models that follow the time course and trajectory of humans with ADAD 5–12 . Based on these findings, by 4 to 6 years of age in the marmosets, which is the human age equivalent of 32 to 48 years, we predict we will observe the accumulation of Aβ in their brains with positron emission tomography (PET) neuroimaging and possibly early subtle changes in behavior that herald the onset of mild cognitive impairment 5–12,21 . Neuroimaging studies are in progress, including extensive validation studies of 11 C‐PiB‐PET for amyloid and 18 F‐AV‐1451‐PET for Tau, for which there have been no published validated protocols to date in marmosets and which we are currently establishing and optimizing 21 .…”

“…While this report describes the generation of these marmoset models and initial early phenotypic characterization data, which are already revealing novel insights into molecular changes that precede frank neuropathology as a result of these PSEN1 mutations, comprehensive characterization of these models and their germline lineages is ongoing as part of the MARMO‐AD consortium 21 . MARMO‐AD is applying the NIA‐Alzheimer's Association research framework to characterize the disease trajectory of the marmosets from birth throughout their lifespan 21,67–69 .…”

“…Here, we report that marmosets with PSEN1 KI point mutations display this hallmark of EOAD, and this phenotype is conserved in their germline offspring, consistent with ADAD mutations in humans. These marmosets are being comprehensively studied as part of the National Institute on Aging (NIA)‐funded Marmosets as Research Models for Alzheimer's Disease (MARMO‐AD) Consortium, which aims to bridge the rodent‐to‐human translational gap to identify primate‐specific mechanisms that drive AD pathogenesis 21 . Importantly, the comprehensive study of these founder marmosets and their germline offspring longitudinally from birth throughout their lifespan will provide fundamental knowledge in our understanding of the biological processes that precede the known cascade of events and will enable the discovery of mechanisms that underlie AD inception and pathogenesis, as well as serving as model systems for evaluating interventions that have the potential to stop and prevent the onset of disease.…”

Marmosets as model systems for the study of Alzheimer’s disease and related dementias: substantiation of physiological Tau 3R and 4R isoform expression and phosphorylation

“…Non-human primates provide critical insight into primate-specific mechanisms that are the etiologies of human diseases. Given the translational limitations of rodent models, the common marmoset (Callithrix jacchus) has emerged as an important model system for studying diseases of aging, including Alzheimer's disease (AD) [1][2][3][4][5]. The marmoset brain has conserved neuroanatomical and neurocircuitry to that of humans [6,7], as well as age-related cognitive decline and neuropathological features that align with postmortem tissues of human AD patients [1,8,9] One of the major pathological hallmarks of AD, amyloid-beta (Aβ) deposition in the brain has also been reported frequently in marmosets as early as 7 years of age, which is equivalent to a 56-year-old human [8].…”