The Role of Insulin Signaling in Hippocampal-Related Diseases: A Focus on Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a global concern and has become a major public health event affecting human health. Insulin is a metabolic hormone secreted mainly by the peripheral tissue pancreas. In recent years, more and more evidence has proved that insulin regulates various functions of the brain. The hippocampus, one of the earliest brain regions affected by AD, is widely distributed with insulin receptors. Studies have shown that type 2 diabetes mellitus, characterized by insulin resistance, is closely related to AD, which has drawn extensive attention to the relationship between hippocampal insulin signaling and AD. Therefore, we provide an overview of intranasal insulin administration on memory and its underlying mechanism. We also highlight the molecular link between hippocampal insulin resistance and AD and provide a theoretical basis for finding new therapeutic targets for AD in clinical practice.

Keywords: hippocampus; insulin resistance; memory impairment; type 2 diabetes mellitus.

Figure 1

Schematic diagram showing the possible sources of brain insulin. First, the BBB is composed of a capillary basement membrane, pericytes, astrocytes, and specialized capillary endothelial cells that are interconnected with tight junctions. Peripheral insulin can cross the BBB intact through IR-specific vesicle-mediated transport in endothelial cells. Second, the B-CSF barrier has fenestrated capillaries in the choroid plexus that lack tight junctions and allow para- and trans-cellular transport across the endothelium. The B-CSF barrier is another possible route for insulin to enter the CNS. Third, there is some limited evidence suggesting the possibility of de novo insulin synthesis in the brain. BBB: blood-brain barrier, BISF: brain interstitial fluid, CSF: cerebrospinal fluid; IR: insulin receptor.

Figure 2

Association between hippocampal pathology and AD disease. AD is characterized by the accumulation of Aβ and hyperphosphorylation of tau protein which lead to neuronal degeneration and changes in synaptic structure and function, leading to neurotoxicity. The damage of mitophagy can lead to the reduction in mitochondrial quality and abnormal mitochondrial function. On the one hand, it promotes the progression of AD pathology. On the other hand, the abnormal mitochondrial function also leads to increased ROS release, which may further lead to hippocampal iron accumulation and neuroinflammation, and then lead to Aβ accumulation and hyperphosphorylation, which may eventually lead to neurotoxicity and AD. AD: Alzheimer’s disease, LIP: Labile iron pool, Aβ: Amyloid beta, NFTs: Neurofibrillary tangles, √: Protective effect, ×: Damaging effect (Drawn by Figdraw).

Figure 3

A molecular link between insulin resistance and AD. Insulin resistance contributes to the development of AD pathology through both direct and indirect pathways. Brain insulin resistance reduces IDE levels and insulin signaling directly induces Aβ deposition and tau hyperphosphorylation. In addition, insulin resistance-induced neuroinflammation and oxidative stress are also involved in the regulation of AD pathological progression. IR: insulin receptor, IDE: insulin-degrading enzyme, Aβ: amyloid beta, NFTs: neurofibrillary tangles, ×: inhibiting effect (Drawn by Figdraw).