The Role of Nerve Growth Factor in Type 2 Diabetes and Alzheimer’s Disease in the C57BL/6N Mouse Model

Abstract

Both obesity and type 2 diabetes mellitus (T2DM) are chronic diseases that are caused by metabolic dysregulations. Disturbance of metabolism homeostasis can further lead to the development of neurodegenerative diseases, such as Alzheimer’s disease (AD). Nerve growth factor (NGF) is a neurotrophic factor and plays multiple roles in the central nervous system, including cell proliferation, survival, and apoptosis. Therefore, the goal of this study was to explore the role of NGF in regulating brain disorders and thus the progression of AD induced by both obesity and T2DM. First, mice were given either a chow diet or a high-fat diet plus sugar-sweetened drinking water (HFS). Half of the HFS mice were further treated with low doses of streptozotocin (STZ). The occurrence of insulin resistance but not hyperglycemia indicated the development of obesity in HFS mice, while the occurrence of both insulin resistance and hyperglycemia indicated the development of T2DM condition in HFS+STZ mice. Next, the Western Blot technique was applied to detect the protein levels in the mouse brain. We demonstrated that the insulin signaling proteins altered by HFS and HFS+STZ treatment were restored by intranasal-delivered NGF, possible mechanisms included reducing insulin receptor loss, activating insulin signaling, and alleviating abnormal insulin degradation. NGF thus mitigated the associated progression of AD, by reducing the accumulations of both amyloid-beta and hyper-phosphorated tau protein. Finally, Hematoxylin and Eosin staining, immunofluorescence, and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling assay were recruited to determine the effect of NGF on other pathologies that are linked to both T2DM and AD. NGF exerted neuroprotective effects on attenuating neuroinflammation, mitochondrial dynamics dysregulation, and mitochondria-mediated apoptosis induced by HFS and HFS+STZ. Taken together, we demonstrated that intranasal NGF administration was a promising method to rescue the neuronal insulin signaling proteins, inflammation, and cell death impaired by obesity and T2DM. NGF had beneficial effects on alleviating brain damage and AD progression in the context of metabolic disorders. NGF has the potential to serve as an AD modifying treatment.