Brains of rhesus monkeys display Aβ deposits and glial pathology while lacking Aβ dimers and other Alzheimer's pathologies.

Jing Zhang,Jing Lu,Liming Zhu,Baian Chen,Cuibai Wei,Zitong Yao,Yanhua Qiao,Yi Wu,Wei Qin,Shubo Wang,Jianping Jia,Quan Sun,Qiao Zhao

doi:10.1111/acel.12978

Abstract

Cerebral amyloid beta (Aβ) deposits are the main early pathology of Alzheimer's disease (AD). However, abundant Aβ deposits also occur spontaneously in the brains of many healthy people who are free of AD with advancing aging. A crucial unanswered question in AD prevention is why AD does not develop in some elderly people, despite the presence of Aβ deposits. The answer may lie in the composition of Aβ oligomer isoforms in the Aβ deposits of healthy brains, which are different from AD brains. However, which Aβ oligomer triggers the transformation from aging to AD pathogenesis is still under debate. Some researchers insist that the Aβ 12‐mer causes AD pathology, while others suggest that the Aβ dimer is the crucial molecule in AD pathology. Aged rhesus monkeys spontaneously develop Aβ deposits in the brain with striking similarities to those of aged humans. Thus, rhesus monkeys are an ideal natural model to study the composition of Aβ oligomer isoforms and their downstream effects on AD pathology. In this study, we found that Aβ deposits in aged monkey brains included 3‐mer, 5‐mer, 9‐mer, 10‐mer, and 12‐mer oligomers, but not 2‐mer oligomers. The Aβ deposits, which were devoid of Aβ dimers, induced glial pathology (microgliosis, abnormal microglia morphology, and astrocytosis), but not the subsequent downstream pathologies of AD, including Tau pathology, neurodegeneration, and synapse loss. Our results indicate that the Aβ dimer plays an important role in AD pathogenesis. Thus, targeting the Aβ dimer is a promising strategy for preventing AD.

Highlights

Alzheimer's disease (AD), the most common type of dementia, is a chronic and progressive neurodegenerative disease
Progress toward developing effective AD treatments may be greatly improved by clarifying the key molecules involved in the pathogenesis of AD
Previous reports suggest that Aβ oligomers in Aβ deposits are the main toxic isoforms that trigger the subsequent downstream pathogenic events associated with AD (Cline, Bicca, Viola, & Klein, 2018; Selkoe & Hardy, 2016)

Summary

| INTRODUCTION

Alzheimer's disease (AD), the most common type of dementia, is a chronic and progressive neurodegenerative disease. The GFAP intensity in the cerebral cortex of old monkeys was significantly higher than that of young monkeys (p = 0.001 in FR, p < 0.001 in OC, Figure 3b) These results suggest that natural Aβ deposits in the brain during normal aging may induce gliosis (including microgliosis and astrocytosis) in monkeys. To determine whether spontaneously developed cer‐ ebral Aβ deposits induce neuronal loss during normal aging, we performed Nissl staining on continuous brain sections of young and old rhesus monkeys containing Aβ deposits (Figure 1a). Our results indicate that brains of rhesus monkeys lacking Aβ dimers did not show neurodegeneration, synapse loss, or working memory impairment

| DISCUSSION

Findings

| EXPERIMENTAL PROCEDURES