The aged rhesus macaque manifests Braak stage III/IV Alzheimer's‐like pathology

Abstract

The aging rhesus macaque provides the long-sought animal model for exploring the etiology of late-onset Alzheimer's disease and for testing preventive strategies.

Synaptic distributions of pS214‐tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline

“…When frequency data were collapsed across age and treatment groups, we found that pS214‐tau was highly enriched in the cytoplasm of both axon terminals and spines. Many cytoplasmic tau immunogold particles were associated with lipid‐rich endomembranous structures (e.g., the spine apparatus), closely mirroring recent observations by others (Carlyle et al, ; Paspalas et al, ). In spines, pS214‐tau reactivity was also prevalent in the synaptic domain.…”

“…Similar to patterns of synaptic distributions of pS214‐tau observed by others, and favoring roles for tau in mediating interactions between N‐methyl‐D‐aspartate (NMDA) receptors and the PSD, and in feedforward calcium signaling, p‐tau was also relatively abundant within the synaptic and cytoplasmic domains of dendritic spines (Carlyle et al, ; Frandemiche et al, ; L. M. Ittner et al, ; Mondragon‐Rodriguez et al, ; Paspalas et al, ; Roberson et al, ; Salter & Kalia, ). In addition, it was often observed at the spine apparatus, as well as other endomembranous structures across the synaptic complex, consistent with earlier reports (Carlyle et al, ; Paspalas et al, ; data not shown). Dendritic spine subsynaptic and plasmalemmal bins each contained ~6% of p‐tau immunogold particles; the localization of tau within these domains supports its proposed interactions with multiple different signaling molecules, the actin cytoskeleton, and the lipid‐rich domains such as the plasma membrane (Y. Wang & Mandelkow, ).…”

“…Pre‐ and postsynaptic localizations of pathological tau species have been previously documented in aged monkey forebrain, and the presence of p‐tau in Area 46 of young monkeys has also been recently described (Carlyle et al, ; Hartig et al, ; Oikawa, Kimura, & Yanagisawa, ; Paspalas et al, ). Here, the majority of axon terminals (~90%) and dendritic spines (~85%) contained p‐tau immunogold particles.…”

“…A substantial literature now supports that several p‐tau species are synaptotoxic, and recent studies suggests that pS214‐tau may specifically contribute to synaptic vulnerability in aged monkey dlPFC (Carlyle et al, ; Crimins, Pooler, Polydoro, Luebke, & Spires‐Jones, ; Paspalas et al, ; Y. Wang & Mandelkow, ). Bivariate Pearson's correlations were used to evaluate possible relationships between synapse density, and synaptic p‐tau distributions.…”

“…A high level of tau phosphorylated at serine 214 (pS214-tau) accumulates in AD brain, and was recently documented within layer III dlPFC dendritic spines of aged, surgically intact rhesus monkeys susceptible to compromised dlPFC network function, and poor working memory performance (Augustinack, Schneider, Mandelkow, & Hyman, 2002;Carlyle et al, 2014;Jicha et al, 1999;Paspalas et al, 2017). Though synaptic p-tau was qualitatively extensive, tau fibrillation was sporadic, and was identified only in dlPFC from the very oldest monkeys.…”