Hypothalamic and hippocampal transcriptome changes in AppNL-G-F mice as a function of metabolic and inflammatory dysfunction

• DOI: 10.1016/j.neuroscience.2024.07.007
• Publication Date: 2024-07-14T06:14:19Z
• Authors: Evelyn Gutiérrez ...; Patricia Joseph; Christos Noutsos; Kinning Poon
• Keywords: Male; Inflammation; Mice; Disease Models, Animal; Amyloid beta-Protein Precursor; Alzheimer Disease; Hypothalamus; Animals; Mice, Transgenic; Cognitive Dysfunction; Transcriptome; Hippocampus

The progression of Alzheimer's disease (AD) has a silent phase that predates characteristic cognitive decline and eventually leads to active cognitive deficits. Metabolism, diet, and obesity have been correlated to the development of AD but is poorly understood. The hypothalamus is a brain region that exerts homeostatic control on food intake and metabolism and has been noted to be impacted during the active phase of Alzheimer's disease. This study, in using an amyloid overexpression AppNL-G-F mouse model under normal metabolic conditions, examines blood markers in young and old male AppNL-G-F mice (n = 5) that corresponds to the silent and active phases of AD, and bulk gene expression changes in the hypothalamus and the hippocampus. The results show a large panel of inflammatory mediators, leptin, and other proteins that may be involved in weakening the blood brain barrier, to be increased in the young AppNL-G-F mice but not in the old AppNL-G-F mice. There were also several differentially expressed genes in both the hypothalamus and the hippocampus in the young AppNL-G-F mice prior to amyloid plaque formation and cognitive decline that persisted in the old AppNL-G-F mice, including GABRa2 receptor, Wdfy1, and several pseudogenes with unknown function. These results suggests that a larger panel of inflammatory mediators may be used as blood markers to detect silent AD, and that a change in leptin and gene expression in the hypothalamus exist prior to cognitive effects, suggesting a coupling of metabolism with amyloid plaque induced cognitive decline.