Nonhuman primates as the animal model for age-dependent diseases

Abstract

The dramatic advances in medical care have enabled human beings to live longer lives. However, we never avoid aging ourselves, and aging also causes the agedependent disorders itself. Now that we encounter the longevity century, age-dependent disorders have become one of the biggest problems in the world. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by two pathological hallmarks, senile plaques (SPs) and neurofibrillary tangles (NFTs). SPs are mainly composed of amyloid-β protein (Aβ) generated from amyloid precursor protein (APP). NFTs mainly consist of filaments of hyperphosphorylated tau that is one of the microtubule-associated proteins. Accumulating evidence suggests that AD is categorized into two types, familial AD (FAD) and sporadic AD (SAD). FAD is caused by mutations of certain causative genes such as presenilins (PSs) and APP, resulting in early-onset AD. On the other hand, SAD is an age-dependent neurodegenerative disease, resulting in late-onset AD. In past decades, numerous neuroscientists have been investigating molecular pathology of AD, however, it still remains unclear why aging causes SAD. In the case of FAD, causative genetic mutations likely accelerate Aβ assembly through enhanced Aβ generation. However, currently, there is as yet no evidence that Aβ generation is accelerated in SAD, suggesting that the pathogenesis of SAD may be different from that of FAD. Moreover, more than 80% AD patients belong to SAD, and then it is quite important to elucidate the etiology of SAD. Since aging is the most important and critical risk factor for SAD, it is indispensable to clarify "what" and "how" aging affects central nervous system. Nowadays, quite a lot of AD researchers are using causative gene-transgenic animals and -transfected cells. They are really powerful and useful experimental tools to investigate molecular pathology of FAD but not for SAD. Cynomolgus monkey is a nonhuman primate that is much homologous to human rather than other experimental animals such as rodents. In aged cynomolgus monkey brain, SPs are spontaneously observed in the neocortex and consistently at ages over 25. Furthermore, we have previously reported that AD-associated proteins such as APP, tau, and intracellular Aβ accumulate in aged monkey brain. Thus, the cynomolgus monkey is considered to be a useful animal model to investigate age-dependent AD pathology. In this review, I summarize our data and discuss the possibility of nonhuman primates as useful animal models for longevity science.