Quantitative analysis of synaptic pathology and neuroinflammation: an initial study in a female rhesus monkey model of the “synaptic” phase of Alzheimer’s disease

Beckman, Danielle; Donis-Cox, Kristine; Ott, Sean; Roberts, Mary T.; Novik, L; Wg, Janssen; Bliss‐Moreau, Eliza; Rudebeck, Peter H.; Mg, Baxter

doi:10.1101/251025

Cited by 2 publications

(3 citation statements)

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“…Our group recently showed that repeated intracerebroventricular injections of soluble oligomers of the Aβ peptide (AβO) triggers severe spine synapse loss and neuroinflammation, together with increased cerebrospinal fluid levels of Aβ 1‐42 and p‐tau in dlPFC and hippocampus of female rhesus monkeys. Hence, exogenous AβO administration could be fundamental to establishing a nonhuman primate model of early AD pathogenesis (Beckman et al, ).…”

Section: Discussionmentioning

confidence: 99%

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

Crimins

Puri

Calakos

et al. 2018

J of Comparative Neurology

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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.

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Section: Discussionmentioning

confidence: 99%

“…Hence, exogenous AβO administration could be fundamental to establishing a nonhuman primate model of early AD pathogenesis (Beckman et al, 2018).…”

Section: Synaptic Ps214-tau and Cognitive Statusmentioning

confidence: 99%

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

Crimins

Puri

Calakos

et al. 2018

J of Comparative Neurology

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“…These changes to the brain are region specific. Previous studies have reported that the prefrontal cortex (PFC) is one the regions most affected by age, with significant decrease in synaptic density and cortical layer thickness [6,[15][16][17][18][19]. PFC plays an important role in working memory function, selfregulatory and goal-directed behaviors, all of which are vulnerable to aging [20].…”

Section: Introductionmentioning

confidence: 99%

Age-related cognitive decline in baboons: modeling the prodromal phase of Alzheimer's disease and related dementias

Lizarraga

Daadi

Roy-Choudhury

et al. 2020

Aging

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The aging of brain cells and synaptic loss are the major underlying pathophysiological processes contributing to the progressive decline in cognitive functions and Alzheimer's disease. The difference in cognitive performances observed between adult and aged subjects across species highlights the decline of brain systems with age. The inflection point in age-related cognitive decline is important for our understanding of the pathophysiology of neurodegenerative diseases and for timing therapeutic interventions. Humans and nonhuman primates share many similarities including age-dependent changes in gene expression and decline in neural and immune functions. Given these evolutionary conserved organ systems, complex human-like behavioral and age-dependent changes may be modeled and monitored longitudinally in nonhuman primates. We integrated three clinically relevant outcome measures to investigate the effect of age on cognition, motor function and diurnal activity in aged baboons. We provide evidence of a naturally-occurring age-dependent precipitous decline in movement planning, in learning novel tasks, in simple discrimination and in motivation. These results suggest that baboons aged ~20 years (equivalent to ~60 year old humans) may offer a relevant model for the prodromal phase of Alzheimer's disease and related dementias to investigate mechanisms involved in the precipitous decline in cognitive functions and to develop early therapeutic interventions.

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Quantitative analysis of synaptic pathology and neuroinflammation: an initial study in a female rhesus monkey model of the “synaptic” phase of Alzheimer’s disease

Abstract: Background: Soluble oligomers of the Aβ peptide (AβOs) are toxins that target and disrupt synapses.

Cited by 2 publications

References 30 publications

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

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

Age-related cognitive decline in baboons: modeling the prodromal phase of Alzheimer's disease and related dementias

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