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

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, nonhuman 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. 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 with 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.

The protein kinase CK1: Inhibition, activation, and possible allosteric modulation

“…In the context of neurodegeneration, and for Alzheimer’s disease in particular, a number of protein kinases have been involved with relevance to different key pathways ( Flajolet et al, 2007 ; Bustos et al, 2017a ; Bustos et al, 2017b ). For example, tau hyper-phosphorylation is directly linked to tau pathology and a great deal of effort is being devoted to reduce tau hyperphosphorylation ( Rubenstein et al, 2019 ; Wakeman et al, 2022 ); for a recent review see ( Wegmann et al, 2021 ). About 30 phosphorylation sites have been found to be phosphorylated only in normal brain samples and the specific nature of the sites involved might be less important than the overall level of phosphorylation, the overall net charge of tau.…”

Characterization of cerebrospinal fluid biomarkers associated with neurodegenerative diseases in healthy cynomolgus and rhesus macaque monkeys

“… 15 , 16 As many neurodegenerative disorders involve impairment of higher cognitive functions, monkeys have the potential to advance our knowledge of these disorders and validate treatments. Several non‐human primate (NHP) models of AD and aging are being developed, 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 but only a subset have characterized biomarker levels in CSF and how they change in the disease model. 17 , 18 , 19 , 21 , 22 , 23 , 25 …”

“…for a review), aging animals for > 20 years when AD‐related pathology becomes evident is inefficient for mass preclinical drug testing—housing and maintenance of NHPs is expensive and not all will go on to develop the hallmarks of AD. Therefore, induced models being developed 26 (e.g., Beckman et al 23 . and Forny‐Germano et al 24 …”

“…While natural aging in NHPs is a robust model exhibiting features similar to human AD (see Frye et al 38 for a review), aging animals for > 20 years when AD-related pathology becomes evident is inefficient for mass preclinical drug testinghousing and maintenance of NHPs is expensive and not all will go on to develop the hallmarks of AD. Therefore, induced models being developed 26 (e.g., Beckman et al 23 and Forny-Germano et al 24 ) may provide another option and could use younger animals. Given the limited number of animals often used in many NHP studies, it is difficult to interpret pathological CSF changes in models of neurodegenerative disease without having good reference ranges with which to compare.…”

“…15,16 As many neurodegenerative disorders involve impairment of higher cognitive functions, monkeys have the potential to advance our knowledge of these disorders and validate treatments. Several non-human primate (NHP) models of AD and aging are being developed, [17][18][19][20][21][22][23][24][25][26] but only a subset have characterized biomarker levels in CSF and how they change in the disease model. [17][18][19][21][22][23]25 Macaques reach sexual maturity between 3 and 4 years in females 27,28 and 3 to 6 years in males 28,29 and maturity is typically earlier in captivity than in the wild.…”