Title

Intrathecal amyloid-beta oligomer administration increases tau phosphorylation in the medial temporal lobe in the African green monkey: a nonhuman primate model of Alzheimer's disease

Document Type

Article

Abstract

AIMS: An obstacle to developing new treatment strategies for Alzheimer's disease (AD) has been the inadequate translation of findings in current AD transgenic rodent models to the prediction of clinical outcomes. By contrast, non-human primates (NHPs) share a close neurobiology with humans in virtually all aspects relevant to developing a translational AD model. The present investigation used African green monkeys (AGMs) to refine an inducible NHP model of AD based on the administration of amyloid-beta oligomers (AβOs), a key upstream initiator of AD pathology. MATERIALS AND METHODS: AβOs or vehicle were repeatedly delivered over 4 weeks to age-matched young adult AGMs by intracerebroventricular (ICV) or intrathecal (IT) injections. Induction of AD-like pathology was assessed in subregions of the medial temporal lobe (MTL) by quantitative immunohistochemistry (IHC) using the AT8 antibody to detect hyperphosphorylated tau. Hippocampal volume was measured by magnetic resonance imaging (MRI) scans prior to, and after, intrathecal injections. RESULTS: IT administration of AβOs in young adult AGMs revealed an elevation of tau phosphorylation in the MTL cortical memory circuit compared to controls. The largest increases were detected in the entorhinal cortex that persisted for at least 12 weeks after dosing. MRI scans showed a reduction in hippocampal volume following AβO injections. CONCLUSIONS: Repeated IT delivery of AβOs in young adult AGMs led to an accelerated AD-like neuropathology in MTL, similar to human AD, supporting the value of this translational model to de-risk the clinical trial of diagnostic and therapeutic strategies.

Keywords

African green monkey, Alzheimer’s disease, amyloid-beta oligomer, entorhinal cortex, hippocampus, intrathecal, phosphorylated Tau

Publication Date

2-14-2022

Publication Title

Neuropathology and applied neurobiology

E-ISSN

1365-2990

PubMed ID

35156715

Digital Object Identifier (DOI)

10.1111/nan.12800

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