A mass-producible macaque model displays a durable Alzheimer-like cognitive deficit and hallmark amyloid-β/tau/neurofilament light chain pathologies.

Abstract

BackgroundAlzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive deficit and pathological accumulation of amyloid-β (Aβ) and tau proteins. The rodent models have contributed greatly to unravel AD pathogenesis, but these AD models have been shown a modest clinical translational effectiveness.ObjectiveTherefore, developing mass-producible primate AD models is promising for more effective drug development.MethodsHere, we constructed the AD monkey models by simultaneously infusing AAV-Tau and Aβ into different brain regions.ResultsThe induced monkeys showed a durable cognitive impairment lasting for at least 10 months after the modeling. Simultaneously, the increased levels of total tau and hyperphosphorylated tau (pTau) at several AD-associated sites, and neurofilament light chains (NfL) with altered Aβ level were detected at different time points in cerebrospinal fluid and/or plasma by using MSD kits. The increased brain accumulation of Aβ and tau proteins was also detected by positron emission tomography/magnetic resonance imaging and immunohistochemical staining. The model monkeys also had significant glial activation; an indicator of inflammation commonly seen in the brains of AD patients.ConclusionsTogether, this study provides mass-producible monkey models showing durable AD-like hallmark pathologies (Aβ, tau, NfL, i.e., ATN) and cognitive deficits. As monkeys are genetically and metabolically the closest to humans, these models will offer more effective drug discovery and development for AD.