Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels

Abstract

Introduction Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes. Methods We examined whether APP/PS1 mice exhibit increased susceptibility to aging or high-fat diet (HFD)-induced metabolic impairment using metabolic phenotyping and insulin-signaling studies. Results APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling. Discussion Our data suggest that AD pathology increases susceptibility to diabetes due to impaired hypothalamic insulin signaling, and that plasma BCAA levels could serve as a biomarker of hypothalamic insulin action in patients with AD.

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

“…The exact mechanism that leads T2D to cause cognitive dysfunction and dementia, or conversely, the role of AD on the induction of diabetes has not been clearly established. It is known that hyperglycemia and insulin resistance can cause structural changes in the hippocampus and hypothalamus, which are involved in regulating carbohydrate metabolism and branched chain amino acid homeostasis, which are impaired in patients with AD [60]. A clear relationship between AD and T2D has been established by the fact that mice with induced IDE deficiency exhibited both AD and T2D symptoms [34], [35] and similarly findings were reported in humans [30], [61], [63].…”

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

“…Metabolic regulation occurs via modulation of vagal and/or sympathetic efferent fibres, and vagotomy or sympathectomy abrogates suppression of hepatic glucose production or adipose tissue lipolysis, respectively 107,110 . Together, these studies show that the association between T2DM and brain dysfunction might be due to impaired hypothalamic insulin action resulting in disrupted metabolic control and increasing susceptibility to T2DM due to whole-body insulin resistance 113 .…”

Metabolic network failures in Alzheimer's disease: A biochemical road map

“…Low levels of BCAAs have been implicated in hepatic insulin resistance in liver disease and may have a broader role in insulin resistance in the brain [77]. The seemingly paradoxical directionality difference in correlation of BCAAs with diabetes and cognition needs to be further evaluated in longitudinal studies taking into account weight changes, tissue type, and differences in human and animal model systems [28,78]. Our understanding of the biochemical crossroads between diabetes and AD could be greatly enhanced by metabolic profiling of both central and peripheral tissues in both diseases and over time.…”