Background: Individuals with mild cognitive impairment (MCI) have reduced lipid-stimulated mitochondrial respiration in skeletal muscle. A major risk factor for Alzheimer’s disease (AD), the apolipoprotein E4 (APOE4) allele, is implicated in lipid metabolism and is associated with metabolic and oxidative stress that can result from dysfunctional mitochondria. Heat shock protein 72 (Hsp72) is protective against these stressors and is elevated in the AD brain. Objective: Our goal was to characterize skeletal muscle ApoE and Hsp72 protein expression in APOE4 carriers in relationship to cognitive status, muscle mitochondrial respiration and AD biomarkers. Methods: We analyzed previously collected skeletal muscle tissue from 24 APOE4 carriers (60y+) who were cognitively healthy (CH, n = 9) or MCI (n = 15). We measured ApoE and Hsp72 protein levels in muscle and phosphorylated tau181 (pTau181) levels in plasma, and leveraged previously collected data on APOE genotype, mitochondrial respiration during lipid oxidation, and VO2 max. Results: Muscle ApoE (p = 0.013) and plasma pTau181 levels (p < 0.001) were higher in MCI APOE4 carriers. Muscle ApoE positively correlated with plasma pTau181 in all APOE4 carriers (R2 = 0.338, p = 0.003). Hsp72 expression negatively correlated with ADP (R2 = 0.775, p = <0.001) and succinate-stimulated respiration (R2 = 0.405, p = 0.003) in skeletal muscle of MCI APOE4 carriers. Plasma pTau181 negatively tracked with VO2 max in all APOE4 carriers (R2 = 0.389, p = 0.003). Analyses were controlled for age. Conclusion: This work supports a relationship between cellular stress in skeletal muscle and cognitive status in APOE4 carriers.
This review proposes the novel hypothesis that heat can be used as an alternative therapy to exercise to improve hepatic mitochondrial function and glucose regulation in patients with nonalcoholic fatty liver disease. Although exercise has proven benefits in treating nonalcoholic fatty liver disease, barriers to exercise in the majority of patients necessitate an alternative method of treatment.
BackgroundInsulin resistance is a known risk factor for Alzheimer’s Disease and related dementias (ADRD). While the role of insulin on peripheral tissue is well understood, it’s effect on the brain remains unclear. Insulin and other gastrointestinal peptides can cross the blood‐brain barrier to form ligands in areas involved in metabolic response. Thus, it’s important to understand the relationship between systemic metabolic outcomes, such as meal‐stimulated hormone responses, and plasma biomarkers of ADRD.Method67 Participants (27 ADRD) completed a clinical and cognitive (Uniform Data Set 2.0) examination, meal tolerance test, and MRI scan. Cognitive scores were standardized to z‐scores and averaged to yield a global z‐score. EDTA plasma samples collected during the meal tolerance test were analyzed for glucose and insulin, and responses of peptide tyrosine tyrosine (PYY) and gastric inhibitory polypeptide (GIP) were analyzed in plasma from a subset of samples (n=53) containing DPP4 inhibitor. Further characterization of amyloid beta (Aβ42), pTau 181, Neurofilament light (NFL), and glial fibrillary acidic protein (GFAP) was performed using non‐fasted EDTA plasma on the Simoa HD‐X (Quanterix). We then assessed the relationship between the early metabolic and hormone responses to a mixed meal and baseline plasma ADRD biomarkers.ResultThe study sample consisted of 53.7% females and 43.3% APOE4 carriers with an average age of 74.9±6.3 and 16±3 years of education. All analyses were controlled for age and sex. Aβ42/pTau181, pTau 181, NFL, and GFAP were significantly elevated in ADRD compared to CH individuals (p<0.05) and tracked linearly with global cognitive z score (p=0.004, p<0.001, p<0.01, p=0.02, respectively). Linear regression revealed that both pTau 181 (β=0.334, p=0.009) and NFL (β=0.320, p=0.003) tracked significantly with the early PYY response (0‐30 minute), but not other metabolic responses, across the entire cohort. pTau181 and the Aβ42/pTau181 ratio each tracked significantly with global cognitive z score (p<0.001, p=0.01, respectively).ConclusionEarly PYY response to a mixed meal tracks with pTau181 and NFL, plasma biomarkers of ADRD neuropathology and neurodegeneration, respectively. The relationship between gut and brain biomarkers warrants additional study, and further characterization of cross‐sectional and longitudinal relationships with other meal‐related hormone responses is ongoing.
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