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Mid‐life obesity and metabolic dysfunction in a genetically diverse mouse model of Alzheimer’s disease
Author(s) -
Dunn Amy R.,
Hadad Niran,
Kaczorowski Catherine C.,
O'Connell Kristen M.S.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.044038
Subject(s) - leptin , obesity , metabolic syndrome , medicine , endocrinology , disease , dementia , genetically modified mouse , physiology , appetite , alzheimer's disease , biology , transgene , genetics , gene
Background Age and genetic background are the greatest risk factors for Alzheimer’s disease, but obesity and metabolic syndrome increase the risk of developing AD, as increased BMI at mid‐life is associated with an earlier age at onset for AD dementia. Furthermore, many AD patients also present with non‐cognitive symptoms associated with metabolic dysfunction, such as weight loss, changes in appetite, and low circulating leptin levels, which often occur prior to the onset of cognitive decline. Thus, systemic metabolic function may be an important, causal factor in the etiology of AD in humans. However, the mechanisms underlying this dysfunction and its relationship to disease onset, progression, and severity are poorly understood. Methods We assessed metabolic function in mice from our recently developed model of human AD, the AD‐BXD genetic reference panel (Neuner, et al 2019). Metabolic function was measured in 39 AD‐ and non‐transgenic (Ntg) strains using indirect calorimetry in Promethion metabolic cages to measure energy expenditure, V O2 and V CO2 , respiratory exchange rate (RER), locomotor activity, food and water intake, and sleep. To model mid‐life obesity, a subset of age‐ and sex‐matched AD‐ and Ntg‐BXD mice were fed a high‐fat/high‐sugar diet (HFD) starting at ∼2.5 months of age. Results AD‐BXD mice weigh less than their non‐transgenic counterparts; assessment of body composition indicates this is due primarily to a loss of fat mass. AD‐BXD strains also exhibited an increase in rearing behavior, which may indicate hypervigilance. Female AD‐BXD strains exhibited increased energy expenditure and locomotor activity and failed to develop diet‐induced obesity when fed HFD. Mice fed HFD generally displayed changes in RER consistent with a shift to fat metabolism; we further observed changes in patterns of food intake. Conclusions Our data indicate that AD‐BXD mice exhibit some degree of metabolic dysfunction and that this is exacerbated by HFD. Analyses indicate that metabolic dysfunction at cognitively presymptomatic ages is correlated with memory deficits later in life. Ongoing work will quantify the impact of genetic background on these traits and relationships between metabolic and cognitive phenotypes.