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

Abstract

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.

Aging‐related Alzheimer's disease‐like neuropathology and functional decline in captive vervet monkeys (Chlorocebus aethiops sabaeus)

“…CSF biomarkers also may be tied to metabolic perturbations. Like humans, some vervets develop prediabetes and type 2 diabetes with age (Kavanagh et al, 2007, 2019), conditions which are associated with increased risk of LOAD (An et al, 2018; Craft, 2012; Ferreira et al, 2018). Vervets, therefore, provide opportunities to explore the relationships between metabolic state and LOAD risk.…”

Nonhuman primates at the intersection of aging biology, chronic disease, and health: An introduction to the American Journal of Primatology Special Issue on aging, cognitive decline, and neuropathology in nonhuman primates

“…(Chaudron, Pifferi, & Aujard, 2021), d (Perret, 1997), e (Hämäläinen et al, 2014), f (Weigl, 2005), g (Gary et al, 2019), h (Abbott & Hearn, 1978), i (Ross, 2019), j (Nishijima et al, 2012;Weigl, 2005), k (Abbott et al, 2003), l (Maclean et al, 2000), m (Philippens et al, 2016), n (Ridley et al, 2006), o (Jorgensen, 2021) & Jorgensen pers. comm., p (Atkins et al, 2014), q (Schmitt et al, 2018), r (Cramer et al, 2018), s (Kavanagh et al, 2019) t (Frye et al, 2021), u (van Wagenen, 1952), v (Plant, 2005), w (Tigges, Gordon, McClure, Hall, & Peters, 1988), x (Upright & Baxter, 2021), y (Stonebarger et al, 2020), z…”

Sulfonylureas target the neurovascular response to decrease Alzheimer’s pathology

“…The copyright holder for this preprint this version posted August 12, 2021. ; https://doi.org/10.1101/2021.08.11.455969 doi: bioRxiv preprint Glucose and lactate measurements. Glucose and lactate measurements from blood and hippocampal ISF were quantified using an YSI 2900 analyzer as previously described [7,84]. Insulin ELISAs.…”

“…Glucose and lactate measurements. Glucose and lactate measurements from blood and hippocampal ISF were quantified using an YSI 2900 analyzer as previously described [7,84]. Insulin ELISAs.…”