Abstract
Oxygen free radical burst is a prominent early event in the pathogenesis of Alzheimer’s disease (AD). Posttranslational modifications of Tau protein, primarily hyper-phosphorylation and truncation, are indicated as critical mediators of AD pathology. This finding is confirmed by the high levels of oxidative stress markers and by the increased susceptibility to oxygen radicals found in cultured neurons and in brains from transgenic animal models expressing toxic Tau forms, in concomitance with a dramatic reduction in their viability/survival. Here, we collect the latest progress in research focused on the reciprocal and dynamic interplay between oxygen radicals and pathological Tau, discussing how these harmful species cooperate and/or synergize in the progression of AD. In this context, a better understanding of the role of oxidative stress in determining Tau pathology, and vice versa, primarily could be able to define novel biomarkers of early stages of human tauopathies, including AD, and then to develop therapeutic strategies aimed at attenuating, halting, or reversing disease progression.
Highlights
By taking advantage of primary neuronal culture, namely cerebellar granule cells (CGCs), an in vitro system in which the main apoptotic steps were well characterized from a temporal and causative point of view, we proposed a molecular mechanism of interaction between
The definitive diagnosis of Alzheimer’s disease (AD) can only be made by examining post mortem brain tissue based on the presence of extracellular neuritic plaques (NPs) formed by Aβ peptides, intracellular neurofibrillary tangles (NFTs) consisting of hyperphosphorylated Tau and truncated Tau protein, Aβ heaps in blood vessels, neuronal loss and synaptic and significant atrophy in specific brain regions involved in cognitive function [47]
The 12A12mAb i.v. delivery exerts a protective action by mitigating the increase in both cytosolic and mitochondrial reactive oxygen species (ROS), the lipid peroxidation (LPx) of the mitochondrial membrane, the decrease in the level of GSH and Nicotinamide Adenine Dinucleotide Phosphate (NADPH) and the increase in NADH level, as well as the oxidative phosphorylation (OXPHOS) and the ATP content. These findings indicate that the neuroprotective effect of Tau immunization involves in part the modulation of oxidative stress (OS) and mitochondrial energetic deficits caused by Tau fragments, known to crucially contribute to the synaptic decline of AD in humans [63]
Summary
Over a century after the first diagnosis, we cannot yet say with certainty what triggers. It follows that the molecular mechanism underlying the pathological Aβ-NH2 hTau interplay on ANT-1 in AD neurons involves: (i) thiol groups present at the active site (see [22]) and (ii) the ROS increase which oxidizes these—SH residues, as in [24], acting as modulators/blockers of NH2 hTau fragment toxicity In this context, the convergence of Tau and Aβ on mitochondria in AD explains why the strategies adopted to modify the pathological forms of Aβ- or Tau- have not individually yielded promising results and, consistently, it highlights potential, new pathway(s) and target(s) for effective mutual therapeutic intervention of early dysfunction in AD. A chain of reactions is generated which spreads very quickly and can involve thousands of molecules, with harmful consequences for all the cells of the organism that age prematurely and that favor diseases and degeneration
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