A nonhuman primate model of Alzheimer’s disease generated by intracranial injection of amyloid-beta42 and thiorphan

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathological changes, including the deposition of amyloid-beta (Aβ) peptide. Aged monkeys have proven to be invaluable in the study of AD, as their brains naturally develop amyloid plaques similar to those in AD brains. However, spontaneous development of AD-like pathologies in aged monkeys is time-consuming, often taking several years. Here, we created an experimentally induced AD model in middle-aged (16-17 years) rhesus monkeys by intracranial injection of Aβ42 and thiorphan, an inhibitor of neprilysin that is responsible for Aβ clearance. The working memory capacity of the monkeys in a delayed-response task was little affected following the delivery of Aβ42 and thiorphan. However, the administration of Aβ42 and thiorphan resulted in a significant intracellular accumulation of Aβ in the neurons of the basal ganglia, the cortex, and the hippocampus, accompanied by neuronal atrophy and loss. Moreover, immunohistochemistry revealed a degeneration of choline acetyltransferase-positive cholinergic neurons and an increase of glial fibrillary acidic protein-positive astrocytes. In conclusion, our data demonstrate a primate model of AD generated by combined infusion of Aβ42 and thiorphan, which duplicates a subset of neuropathological changes in AD brains, thereby having implications in the elucidation of this disease.

Curcumin Inhibits the AKT/NF-κB Signaling via CpG Demethylation of the Promoter and Restoration of NEP in the N2a Cell Line

“…Thus, there may be more mechanisms contributing to the inhibitory effect of CUR on this signaling. In this study, we hypothesize the entire disruption of suppression of AKT/NF-κB signaling by CUR/Thiorphan combination treatment probably due to the higher effect of Thiorphan on activating this signaling because of its ability to exacerbate Aβ accumulation (46,47), thus masking CUR effect. Further, when we tested the proteins known to be downstream targets of NF-κB, we found that CUR reduced protein levels of COX-2 and iNOS in a time-dependent manner.…”

Engineering Neprilysin Activity and Specificity to Create a Novel Therapeutic for Alzheimer’s Disease

“…In animal models manipulation of the levels of brain NEP has been shown to have a significant effect on Aβ levels. Mice deficient in the NEP gene show defects in their ability to degrade both endogenous and exogenously applied Aβ [17] and inhibition of NEP using thiorphan or phosphoramidon results in accumulation of Aβ in rats [18], rabbits [19] and non-human primates [20]. Over-expression of NEP in the brain through transgenic [21] or viral transduction [22]–[24] results in a lowering of Aβ levels in the brain.…”

Selection of Appropriate Reference Genes for RT-qPCR Analysis in a Streptozotocin-Induced Alzheimer’s Disease Model of Cynomolgus Monkeys (Macaca fascicularis)

“…The rhesus monkey ( Macaca mulatta ) and cynomolgus monkey ( Macaca fascicularis ) are widely used animal models for the studying neurodegenerative diseases such as AD, PD, Huntington’s disease, and amyotrophic lateral sclerosis [11]–[15]. However, only a few studies on the selection of suitable reference genes have been performed on the rhesus monkey brain and organs [16]–[18].…”