Metabolism-Centric Overview of the Pathogenesis of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia. AD is characterized by the extracellular amyloid beta (Aβ) plaques and intraneuronal deposits of neurofibrillary tangles (NFTs). Recently, as aging has become a familiar phenomenon around the world, patients with AD are increasing in number. Thus, many researchers are working toward finding effective therapeutics for AD focused on Aβ hypothesis, although there has been no success yet. In this review paper, we suggest that AD is a metabolic disease and that we should focus on metabolites that are affected by metabolic alterations to find effective therapeutics for AD. Aging is associated with not only AD but also obesity and type 2 diabetes (T2DM). AD, obesity, and T2DM share demographic profiles, risk factors, and clinical and biochemical features in common. Considering AD as a kind of metabolic disease, we suggest insulin, adiponectin, and antioxidants as mechanistic links among these diseases and targets for AD therapeutics. Patients with AD show reduced insulin signal transductions in the brain, and intranasal injection of insulin has been found to have an effect on AD treatment. In addition, adiponectin is decreased in the patients with obesity and T2DM. This reduction induces metabolic dysfunction both in the body and the brain, leading to AD pathogenesis. Oxidative stress is known to be induced by Aβ and NFTs, and we suggest that oxidative stress caused by metabolic alterations in the body induce brain metabolic alterations, resulting in AD.

Keywords: Alzheimer's disease; adiponectin; antioxidants; insulin; metabolic disease.

Fig. 1. Alteration of brain metabolism causes Alzheimer's disease. Aging and metabolic diseases, such as obesity and diabetes, can alter brain metabolism. Alteration of brain metabolism progressively causes Alzheimer's disease.

Fig. 2. Brain insulin resistance causes Alzheimer's disease. (A) Insulin signaling maintains normal neuronal functions through IRS, ERK/MAPK, PI3K/AKT, and GSK3 signals. (B) Brain insulin resistance blunts insulin signal transduction, leading to neuronal cell death and Alzheimer's disease. IRS, insulin receptor substrate; ERK/MAPK, extracellular signal-related kinase/mitogen activated protein kinase; PI3K/AKT, PI3 kinase/Akt pathways; GSK3, glycogen synthase kinase-3; IDE, insulin-degrading enzyme; Aβ, amyloid beta.

Fig. 3. Reduced adiponectin levels induce brain metabolism alterations and consequently Alzheimer's disease. (A) Healthy adipose cells release adiponectin actively. Adiponectin regulates glucose metabolism and oxidases fatty acids in the brain in normal conditions. (B) Hypertrophic adipose cells induced by obesity elicit a pro-inflammatory environment and reduce adiponectin production. Reduced adiponectin causes energy shortages in the brain due to reduced fatty acid oxidation and dysregulated glucose metabolism. This induces brain metabolism alterations and progressively leads to Alzheimer's disease. HIF 1α, hypoxia inducible factor 1α.

Fig. 4. 24 weeks of a high fat-diet causes decreases in adiponectin and adiponectin receptors and increases in HIF-1α in the brain. 8-week-old ICR mice were fed a 60% high fat diet for 24 weeks, and the levels of adiponectin, adipoR1 and HIF-1α were examined using western blot analysis. APN and adipoR1 were decreased in the cortices of the mice. HIF-1α increased in both the cortices and hippocampuses of the high fat-fed mice. Four mice were included in each group. ^*p<0.05. adipoR1, adiponectin receptor 1; HIF-1α, hypoxia inducible factor-1α; APN, adiponectin; HMW, high molecular weight; MMW, middle molecular weight; LMW, low molecular weight; ND, normal diet; HFD, high fat diet.

Fig. 5. Oxidative stress induces brain metabolism alterations, resulting in Alzheimer's disease. Persons suffering with metabolic diseases show higher levels of oxidative stress. Increased ROS causes brain metabolism alterations, such as fatty acids peroxidation and lipid synthesis, leading to progressive Alzheimer's disease. ROS, reactive oxygen species.