SfN19: Metabolic disturbances in the brain may exacerbate and forewarn Alzheimer’s pathology in mice

Written by Sharon Salt, Editor

Recent research has implicated that Type 2 diabetes could increase the risk of Alzheimer’s disease (AD) by twofold. As metabolism of glucose is essential for brain functioning, including energy distribution and neural activity, any malfunction in this system would have cascading effects. Thus, researchers are working to understand the exact mechanisms that underpin the consequences of metabolic disturbances to more easily identify and treat diseases such as AD.  

At SfN Neuroscience 2019 (19–23 October, Chicago, IL, USA), three studies have been presented on the connection between dementia and the metabolic system that fuels the brain. David Holtzman (Washington University, MO, USA), who is the press conference moderator for these sets of abstracts, believes that further research could help us understand how to manipulate these functions for treatment purposes, in addition to identifying the underpinnings of the disease.  

High-fat diet in mice leads to memory impairment and decreased insulin signaling in the brain  

In one abstract presented at the conference, researchers examined the effect of a typical Western diet on the insulin-Akt-GSK3β pathway in male and female mice with different AD-linked genetic backgrounds.  

Within their study, mice were fed with either a typical Western diet or standard diet from 5 months of age. At the age of 11–12 months, they underwent behavioral testing and were then sacrificed at 12 months of age.  

Mice that were on the Western diet were observed to significantly gain more weight and exhibited higher fasting and post-glucose injection blood glucose levels compared with standard-diet mice.  

Biochemical analysis of the hippocampal and cortical samples also revealed decreased phosphorylation of Akt1 and Akt2 kinases, as well as their downstream kinase GSK3β in mice on a Western diet.  

The team believe that their results suggest that a typical Western diet leads to impaired insulin-Akt-GSK3β signaling, which they think partially explains the detrimental effects of a Western diet on learning and memory.  

Abstract: Natunen T, Gabbouj S, Koivisto H et al. High-fat diet leads to memory impairment and decreased insulin-Akt-GSK3β signaling in the brain of transgenic mouse model of Alzheimer’s disease. Presented at: SfN Neuroscience, Chicago, IL, USA, 19–23 October 2019.  

Alzheimer’s-related pathology impairs peripheral glucose tolerance in mice  

In a mouse model that develops AD pathology, scientists have identified a defect in the GLUT1 system, which is the same defect that is present in postmortem human AD brains. The researchers anticipate that a consequence of amyloid-β buildup in the brain is impaired glucose delivery to neurons in the brain.  

Their results revealed that a flaw in glucose delivery to neurons results in extra glucose being present in the blood, which could mimic diabetes. The researchers believe that bolstering glucose delivery may be an effective treatment after amyloid-β has appeared in the brain.  

According to the team, it is possible that this is a mechanism that contributes to why individuals with AD have elevated blood glucose levels (i.e., it’s likely not from an endocrine disruption but instead, it could be a result of a side effect of AD).  

Abstract: Barger SW, Hendrix RD, Ou Y, Davis JE, Allen AR, Childs GV. Alzheimer-related pathology impairs peripheral glucose tolerance by disrupting glucose transporter 1 localization and cerebral glucose delivery. Presented at: SfN Neuroscience, Chicago, IL, USA, 19–23 October 2019.  

Glucose resistance and abnormal sleep patterns are prevalent in AD mice prior to cognitive decline and amyloid plaques 

Another study presented at the conference aimed to determine if AD pathology and glycemic fluctuations synergize to cause sleep loss and peripheral glucose intolerance, thereby increasing the risk of both Type 2 diabetes and AD.  

The response in mice that develop AD pathology to induced hyper- and hypo-glycemia was reported to be abnormal before the appearance of other clinical symptoms, such as cognitive decline and amyloid-β plaques. The glycemic changes also impacted sleeping patterns as a result. 

In their abstract, the researchers stated that: “This study represents a novel approach to defining the dynamic interplay between risk factors for AD and Type 2 diabetes and suggests feedforward loop of disease progression where sleep disruptions can modulate AD and Type 2 diabetes risk by altering the relationship between glucose tolerance, cerebral metabolism, neuronal activity and Aβ/tau levels.”  

Abstract: Carroll CM, Stanley M, Pait M et al. Aging and pathology cause sleep disruptions and altered metabolism in mouse models of Alzheimer’s disease. Presented at: SfN Neuroscience, Chicago, IL, USA, 19–23 October 2019.   

Source: Society for Neuroscience. Metabolic disturbances in the brain exacerbates, may forewarn Alzheimer’s pathology. Press release: www.sfn.org/meetings/neuroscience-2019