[Mechanisms of neurodegeneration in Alzheimer's disease].

Abstract

INTRODUCTION: Recent research into mechanisms of neurodegeneration in Alzheimer's disease has lead to a dramatic increase in our understanding of the mechanisms of cell death and neuroprotection. Alzheimer's disease is a complex disease with multiple etiological factors involved in disease pathogenesis. OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION IN ALZHEIMER'S DISEASE: Amyloid-beta peptide toxicity is mediated at least in part by oxidative stress. Anmyloid-beta peptide directly generates reactive oxygen species in the presence of redox-active metal ions. In Alzheimer's disease, oxidative stress is present early in pathogenesis and contributes to disease pathogenesis. Unlike other organs, the brain is especially vulnerable to reactive oxygen species due to neurons having relatively low levels of endogenous antioxidants. Overly abundant oxygen radicals cause the destruction of cellular macromolecules and participate in signaling mechanisms that result in apoptotic cell death. MICROGLIAL ACTIVATION AND NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE IN ALZHEIMER'S DISEASE: There is a wealth of evidence demonstrating that microglia, the resident innate immune cells in the brain, can become deleterious and damage neurons. Microglial activation causes neuron damage through the production of neurotoxic factors, such as reactive oxygen species and cytokines that are toxic to neurons. The neuron also has strong homeostatic mechanisms that can delay or prevent activation of apoptosis and necrosis. INSULIN RESISTANCE AND ALZHEIMER'S DISEASE: Insulin plays a role in Alzheimer's disease, as it is involved in the metabolism of beta-amyloid. Hyperinsulinemia and type-2 diabetes mellitus results in an increased risk of developing Alzheimer's disease, but its implications when the disease is already well established remain unknown. Treatment of central insulin resistance may be a promising avenue, not only in metabolic syndrom, but also in Alzheimer's disease. CONCLUSION: Increasing evidence suggests a role for oxidative stress, mitochondrial dysfunction, microglial activation and insulin resistance in pathogenesis of neurodegenerative diseases including Alzheimer's disease.