Investigating the molecular and cellular mechanisms explaining the connection between metabolic changes and the deterioration of cognitive function
Authors:
Silvia Penati (1,2), Chiara Adriana Elia (2), Valentina Murtaj (3), Marta Medaglia (2,4), Erica Tagliatti (2), Cecilia Gotti (5), Irene Corradini (1,2), Rosa Maria Moresco (3,6,7), Michela Matteoli (1,2,8), Maria Luisa Malosio (1,2)
Organisations:
1: Institute of Neuroscience, Consiglio Nazionale delle Ricerche (CNR), URTc/o IRCCS Humanitas Clinical and Research Center, Rozzano (MI), Italy
2: Laboratory of Pharmacology and Brain Pathology, Neuro-Center Humanitas Clinical and Research Center, Rozzano (MI)
3: Department of Nuclear Medicine, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
4: University of Pavia, Pavia, Italy
5: Institute of Neuroscience (CNR), Milan, Italy
6: Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza (MB), Italy
7: Institute of Molecular Bioimaging and Physiology, CNR, 20090 Segrate (MI), Italy
8: Humanitas University, Department of Biomedical Sciences, Pieve Emanuele (MI), Italy.
Presenting author:
Maria Luisa Malosio
Exposition date:
Saturday, September 16, 2023
Exposition position:
023/2
Increasing evidence suggests a link between metabolic disorders, such as insulin-resistance and type 2 diabetes, and cognitive decline as well as Alzheimer’s Disease (AD). Changes in peripheral insulin sensitivity due to diet can affect brain cognitive functions. Altered glucose metabolism in the brain, along with high levels of fatty acids and chronic low-grade inflammation, could be the underlying mechanism linking type 2 diabetes and AD.
In this study, an animal model of diet-induced glucose intolerance and insulin-resistance was established to mimic obesity and prediabetes. Mice were fed with 45% and 60% high-fat diets (HFD) for several weeks, and various tests were conducted to evaluate their weight gain, glucose tolerance, insulin tolerance, plasma leptin, and IL6 levels.
The results showed that weight gain increased significantly after only two weeks of HFD consumption, while glucose intolerance became evident after three weeks and insulin-resistance after five weeks. At six weeks of high-fat diet, the mice showed significant changes in anxiety-like behaviors. At later time points (13 weeks), episodic memory was also affected.
Further examination of the hippocampal tissues of mice exposed to HFD revealed altered levels of p-AKT, reduced levels of excitatory subunit receptors, reduced levels of cfos, and elevated levels of markers of endoplasmic reticulum (ER) stress.
PET studies were performed to investigate the brain glucose metabolism.
To investigate the molecular mechanisms responsible for insulin resistance in the brain, palmitate treatments were used on primary neuron cell cultures in vitro to mimic the metabolic conditions induced by HFD.
Overall, the study findings suggest that even short-term exposure (8 and 14 weeks) to HFD can alter relevant brain functions, including neurotransmitter receptors, and induce anxiety and memory deficits at later time points.
