Neurodegenerative disease biomarkers Aβ1–40, Aβ1–42, tau, and p‐tau181 in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy

Chen, Jason; Fears, Scott C.; Jasinska, Anna J.; Huang, Alden; Al‐Sharif, Noor; Scheibel, Kevin; Dyer, Thomas D.; Fagan, Anne M.; Blangero, John; Woods, Roger P.; Jorgensen, Matthew J.; Kaplan, Jay R.; Freimer, Nelson B.; Coppola, Giovanni

doi:10.1002/brb3.903

Cited by 49 publications

(24 citation statements)

References 61 publications

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“…CSF insulin levels were undetectable. Given that decreased CSF Aβ is indicative of increased plaque formation within the brain (Tapiola et al, 2009), these data indicate that T2D monkeys display biomarkers of early amyloid deposition and pre-symptomatic AD (Kalinin et al, 2013; Chen et al, 2018; Latimer et al, 2019) triggered by a state of energy dysregulation, which is consistent with previous work in rodent models (Macauley et al, 2015; Stanley et al, 2016).…”

Section: Resultssupporting

confidence: 89%

“…Monkeys were older, ranging from 16 to 23 years (Table 1), which represents the last 30% of lifespan for this species and is a typical age range for the onset of metabolic diseases and neuropathological changes associated with AD (Kalinin et al, 2013; Chen et al, 2018; Latimer et al, 2019). There were no differences in body weight or waist circumference between groups (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Here, we applied comprehensive metabolic profiling tools to healthy control (Ctrl), pre-diabetic (PreD), and diabetic (T2D) monkeys to explore the relationship between T2D and amyloid pathology. We utilized a cohort of aging vervet monkeys ( Chlorocebus aethiops sabaeus) , which develop neuropathological changes consistent with human AD pathology including increased amyloid plaque burden, elevated cortical tau levels and paired helical filament tau immunoreactivity, Aβ-related vascular impairment, reduced cerebral metabolism, regional atrophy, decreased CSF Aβ 42 and increased CSF tau levels (Kalinin et al, 2013; Chen et al, 2018; Latimer et al, 2019), to ensure translational relevance of our findings. We analyzed plasma and CSF amino acids and acylcarnitine concentrations and explored how these changes related to CSF Aβ 40 and Aβ 42 levels, which are established biomarkers of disease in AD.…”

Section: Introductionmentioning

confidence: 99%

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Type-2-Diabetes Alters CSF but Not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

et al. 2019

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Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer's disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the majority of pathophysiological changes, including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau, occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and amyloid pathology including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, pre-diabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabaeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to PreD and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ 40 and CSF Aβ 42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with previous studies in mice, CSF Aβ 40 and CSF Aβ 42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ 40 and CSF Aβ 42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Type-2-Diabetes Alters CSF but Not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

et al. 2019

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“…Due to their evolutionarily close relationship to humans, NHPs are essential for the study of age-associated changes in the brain and other central nerve system diseases ( Chu et al, 2014 ; Feng et al, 2019 ; Qin et al, 2013 ; Zhang et al, 2014 ). Studies have indicated that CSF levels of Aβ 40 and Aβ 42 decrease significantly with age in cynomolgus and vervet monkeys ( Chen et al, 2018 ; Yue et al, 2014 ). However, no study has investigated the relationship of FA concentrations in CSF samples from different aged rhesus monkeys or the correlation between FA and Aβ levels in CSF samples.…”

Section: Dear Editormentioning

confidence: 99%

Age-associated changes in amyloid-β and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys

Li¹,

He²,

Li³

et al. 2020

Zoological Research

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A: Intergroup analyses of Aβ 40 concentrations. B: Intergroup analyses of Aβ 42 concentrations. C: Intergroup analyses of FA concentrations. D: Correlation between CSF Aβ 40 and FA concentrations in young group ( R =–0.3385, P =0.2172). E: Correlation between CSF Aβ 40 and FA concentrations in middle-aged group ( R =0.02914, P =0.8976). F: Correlation between CSF Aβ 40 and FA concentrations in aged group ( R =–0.5318, P =0.0158). G: Correlation between CSF Aβ 42 and FA concentrations in young group ( R =–0.379, P =0.1635). H: Correlation between CSF Aβ 42 and FA concentrations in middle-aged group ( R =0.4296, P =0.046). I: Correlation between CSF Aβ 42 and FA concentrations in aged group ( R =–0.5344, P =0.0184). Error bars indicate mean± standard deviation ( SD ). *: P <0.05, **: P <0.01, ***: P <0.001. Aβ: β-amyloid; CSF: Cerebrospinal fluid.

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“…The vervet monkey (genus Chlorocebus) is an Old World monkey frequently used as a model in biomedical research (Jasinska et al 2013;Jasinska 2019) particularly for complex chronic diseases, many of which either are associated with aging or aggravate the process of aging. Vervets exhibit some aspects of human aging, including neurodegeneration (Postupna et al 2017;Kalinin et al 2013;Chen et al 2018;Latimer et al 2019), reproductive senescence and menopause (Atkins et al 2014). Vervets have also been used in studies of reproductive physiology and obesity (Kuokkanen et al 2016), the effects of genes and diet on growth and obesity (Schmitt et al 2018), cardiometabolic health (Voruganti et al 2013), physiological and behavioral stress responses Jasinska, Pandrea, et al 2020), and multi-tissue genetic regulation of gene expression, including that in tissues involved in stress responses (Jasinska et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic clock and methylation studies in vervet monkeys

Jasinska

Haghani²,

Zoller³

et al. 2020

Preprint

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DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes hypermethylated with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED, and genes possessing the trimethylated H3K27 mark in their promoters.The epigenetic clocks are expected to be useful for age estimation of wild-born animals and anti-aging studies in vervets.

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Neurodegenerative disease biomarkers Aβ_1–40, Aβ_1–42, tau, and p‐tau₁₈₁ in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy

Cited by 49 publications

References 61 publications

Type-2-Diabetes Alters CSF but Not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

Type-2-Diabetes Alters CSF but Not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

Age-associated changes in amyloid-β and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys

Epigenetic clock and methylation studies in vervet monkeys

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