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

Abstract

Female rhesus monkeys and women are subject to age‐ and menopause‐related deficits in working memory, an executive function mediated by the dorsolateral prefrontal cortex (dlPFC). Long‐term cyclic administration of 17β‐estradiol improves working memory, and restores highly plastic axospinous synapses within layer III dlPFC of aged ovariectomized monkeys. In this study, we tested the hypothesis that synaptic distributions of tau protein phosphorylated at serine 214 (pS214‐tau) are altered with age or estradiol treatment, and couple to working memory performance. First, ovariectormized young and aged monkeys received vehicle or estradiol treatment, and were tested on the delayed response (DR) test of working memory. Serial section electron microscopic immunocytochemistry was then performed to quantitatively assess the subcellular synaptic distributions of pS214‐tau. Overall, the majority of synapses contained pS214‐tau immunogold particles, which were predominantly localized to the cytoplasm of axon terminals. pS214‐tau was also abundant within synaptic and cytoplasmic domains of dendritic spines. The density of pS214‐tau immunogold within the active zone, cytoplasmic, and plasmalemmal domains of axon terminals, and subjacent to the postsynaptic density within the subsynaptic domains of dendritic spines, were each reduced with age. None of the variables examined were directly linked to cognitive status, but a high density of pS214‐tau immunogold particles within presynaptic cytoplasmic and plasmalemmal domains, and within postsynaptic subsynaptic and plasmalemmal domains, accompanied high synapse density. Together, these data support a possible physiological, rather than pathological, role for pS214‐tau in the modulation of synaptic morphology in monkey dlPFC.

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)

“…Therefore, we sought to understand perisynaptic alterations that could render synapses dysfunctional and may distinguish individuals that age without cognitive impairment from those that age with cognitive impairment. Consistent with prior work in aged macaques (Cork et al, 1990;Crimins et al, 2019), we found that aged marmoset presynaptic boutons were larger than young. Furthermore, congruent with the ultrastructural size principle and prior work in aged macaque dlPFC, there were strong linear relationships between synapse and bouton sizes in each of the marmosets.…”

Alzheimer’s-like pathology in aging rhesus macaques: Unique opportunity to study the etiology and treatment of Alzheimer’s disease

“…6F) (7,40). In young monkeys, there is delicate pS214Tau labeling in axons (40), and in the PSD that appears to play a beneficial role (81). However, the large aggregations of pS214Tau near the synapse in aging (7, 40) may interfere with synaptic transmission.…”

Comparative neuropathology in aging primates: A perspective

“…At the ultrastructural level, young macaques (9–11 years, n = 3) showed higher incidence of p‐S214 tau in axons and proximal dendrites, whereas in old macaques (24–31 years, n = 5), it was predominant within dendritic spines, suggesting age‐related trafficking of phosphorylated tau (Carlyle et al, 2014). Moreover, p‐S214 tau within axon terminals and dendritic spines in female rhesus macaques was reduced with age (young 9.9 ± 0.7 years, n = 8 vs. old 25.2 ± 0.9 years, n = 8) and correlated with synapse density but not cognitive status (Crimins et al, 2019).…”