Abstract
BackgroundHypothalamic dysfunction occurs early in the clinical course of Alzheimer’s disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observed years prior to the onset of cognitive symptoms. Late-life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high-fat diet and metabolic disease (e.g., obesity, type 2 diabetes), particularly in mid-life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two-thirds of AD patients, we sought to determine whether these relationships vary by sex.MethodsWT and 3xTg-AD male and female mice were fed a control (10% fat) or high-fat (HF 60% fat) diet from ~ 3–7 months of age, then tested for metabolic and hypothalamic disturbances.ResultsOn control diet, male 3xTg-AD mice displayed decreased body weight, reduced fat mass, hypoleptinemia, and mild systemic inflammation, as well as increased expression of gliosis- and inflammation-related genes in the hypothalamus (Iba1, GFAP, TNF-α, IL-1β). In contrast, female 3xTg-AD mice on control diet displayed metabolic disturbances opposite that of 3xTg-AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin; nonalcoholic fatty liver disease-related pathology). HF diet resulted in the greatest weight gain, adiposity, and glucose intolerance in 3xTg-AD females, which were associated with markedly increased hypothalamic expression of GFAP and IL-1β, as well as GFAP labeling in several hypothalamic nuclei that regulate energy balance. In contrast, HF diet increased diabetes markers and systemic inflammation preferentially in AD males but did not exacerbate hypothalamic inflammation in this group.ConclusionsThese findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg-AD mouse model appears to be dependent on both sex and diet.
Highlights
Hypothalamic dysfunction occurs early in the clinical course of Alzheimer’s disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observed years prior to the onset of cognitive symptoms
AD males weighed less than WT males, while the opposite was seen in females, with AD female mice weighing more than WT female mice
High fat (HF) diet and AD are associated with nonalcoholic fatty liver disease (NAFLD) pathology We evaluated the presence and severity of NAFLD in these mice because of the interrelationship between metabolic disease and NAFLD [67], and because evidence suggests that NAFLD may contribute to AD [53]
Summary
Hypothalamic dysfunction occurs early in the clinical course of Alzheimer’s disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observed years prior to the onset of cognitive symptoms. Cognitive impairment and associated brain regions (e.g., hippocampus, cortex) have been most widely studied, there are numerous non-cognitive symptoms and associated areas of the brain affected that are commonly observed in AD [2] Further exploration of these phenomena is necessary to prevent and/or treat non-cognitive complications of AD, which may further aggravate disease progression, contribute to poor quality of life, and may even be life-threatening. Weight loss is a common clinical feature of AD, reported in up to ~ 40% of cases [6] In both healthy older adults and AD patients, weight loss or low BMI is associated with pathological features of AD, such as increased amyloid burden and CSF biomarkers, as well as cognitive impairment [3, 5, 7,8,9,10], suggesting its utility as a biomarker and possible indicator of disease progression. Weight loss is sometimes seen in AD patients during the prodromal phase, which can be more than a decade prior to cognitive decline [11,12,13], highlighting the possibility of using unintentional weight loss or other metabolic markers as early biomarkers of the disease to identify at-risk individuals
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