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  • br A and tau in Alzheimer s disease

    2024-04-01


    Aβ and tau in Alzheimer's disease The two classical histopathological hallmarks of AD are extracellular insoluble Aβ deposits, known as Aβ plaques, and intracellular accumulations of insoluble microtubule-associated tau protein, known as neurofibrillary tangles [14]. Aβ peptides are produced as a result of the sequential cleavage of the Aβ precursor protein (APP) by the β-secretase (β APP cleavage enzyme – BACE-1) and the γ-secretase complex [composed of the nicastrin, presenilin-1 (PS1), anterior-pharynx defective-1 protein (APH-1), and presenilin enhancer protein-2 (Pen-2)] (Figure 1). APP may be also cleaved by α-secretase (ADAM – a disintegrin and metalloproteinase domain-containing protein) family of proteins and then γ-secretase to produce non-amyloidogenic products, but the Aβ producing pathway is thought to predominate in AD. As Aβ levels rise, soluble Aβ oligomers form, which are precursors to Aβ fibrils, eventually creating insoluble Aβ plaques. Although it was once assumed insoluble plaques cause cellular damage in AD, it is now thought that low-n Aβ oligomers cause neuronal damage and synaptic insult (Figure 1) [15]. In addition to Aβ, the hyperphosphorylation of tau protein is also a crucial event in AD pathogenesis. Tau is thought to serve as a physiological stabilizer of neuronal microtubules, and contributes to axon stability and overall neuronal function [12]. In AD, tau becomes hyperphosphorylated and, by losing its affinity for microtubules, tends to aggregate – eventually forming neurofibrillary tangles (Figure 2). Although tau protein phosphorylation is typically regulated by the balanced action of both tau-associated kinases and phosphatases, in AD two tau-associated kinases are thought to be abnormally functional: cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3B) 16, 17, 18.
    The 12/15LO 12/15LO catalyzes the oxidation of free and esterified fatty acids in phospholipids, generating bioactive lipid mediators such as 12-HETE and 15HETE from arachidonic acid, and 13-hydroxyoctadecadienoic Mithramycin A (13-HODE) from linoleic acid, which have a multitude of functions in human tissue (Figure 3) [19]. 12/15LO lipid products are involved in protein kinase C (PKC)-mediated monocyte binding in vasculature, and in cell growth, acting through various mitogen-activated protein kinases 20, 21. In addition to cell signaling, 12/15LO can initiate oxidation of lipoproteins, and its genetic disruption significantly reduces systemic oxidative stress [22]. 12/15LO-induced oxidative stress and direct cytotoxic effect of its metabolites have been implicated in mitochondrial dysfunction and altered tissue inflammatory responses 23, 24, 25. Furthermore, pharmacological inhibition of this enzyme enhanced the survival of cells that were subjected to nitrosative stress-induced cell death [26]. Although these data provide evidence of the importance of 12/15LO in the periphery, the role of this enzyme in the CNS has only recently received much-deserved attention. In the original report of 12/15LO in the brain, it was described to mainly localize in neurons and also some glial cells throughout the cerebrum, basal ganglia, and hippocampus [27]. Later work showed that the metabolic products of 12/15LO activation were significantly increased in experimental model of brain ischemia–reperfusion injury, and suggested that this enzyme may be involved in neurodegeneration by oxidizing fatty acids in cell membranes [28]. Based on its pro-oxidant properties, this enzyme has been considered a potential source of brain oxidative stress because its genetic absence is sufficient to significantly reduce CNS oxidative stress in APOE-deficient mice, a model of hypercholesterolemia [29]. This role for 12/15LO in the CNS, hitherto underappreciated, has important implications for several neurodegenerative diseases, including AD, in which brain oxidative stress reactions have been shown to be early events in their pathogenesis [30]. Studies using histopathologically confirmed AD postmortem brains demonstrated higher steady-state levels and activity of 12/15LO than in unaffected control brains, while no differences were detected in cerebellar regions between the two groups [31]. Because elevated 12/15 LO expression and activity in AD brains occurs in areas known to be particularly vulnerable to AD insult (i.e., cortex and subcortical structures such as hippocampus), and not in those regions found relatively spared from AD insult, such as cerebellum, these data suggested that 12/15LO might be an AD-relevant molecular target.