Role of Oxidative Damage in Alzheimer's Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

Keywords: Alzheimer’s disease; biomarker; neurodegeneration; oxidative damage.

Figure 1

The neurodegeneration occurring in AD can be related to ROS overproduction and/or a decrease in antioxidant defenses. Aβ deposition can also be directly responsible for ROS increase when it interacts with microglial surface receptors or mitochondria. Mitochondria are the primary source of ROS but also a target of ROS and alteration in energy metabolism have been described in AD patients. ROS may also be considered a second messenger and induce different signaling pathways or the synthesis of antioxidant enzymes (Nrf2). Oxidative damage to mitochondrial DNA and RNA, proteins, and lipids are detected in AD brain. Increased levels of iron and other metals can be responsible of ROS production and iron has been related to ferroptosis. Ca⁺⁺ influx alterations and the consequent mitochondrial dysfunction are also crucial in oxidative damage. Aβ can trigger NO production, an RNS. Oxidative damage affects synapses, causing cognitive impairment in AD. Decreased levels of different lipids have been correlated with cognitive deficit in AD, suggesting their use as biomarkers or in potential clinical intervention.