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    • br Alzheimer s disease AD is an irreversible age associated

    2023-01-29


    Alzheimer’s disease (AD) is an irreversible, age-associated neurodegenerative disorder that is characterized by progressive memory loss and cognitive decline. AD is also the leading cause of dementia, accounting for 5 million cases in the United States and 44 million cases worldwide. In 2015, AD cost >$200 billion in the United States alone and >$600 billion worldwide (). Approximately 5% of AD cases are caused by genetic mutations that are responsible for abnormal amyloid beta (Aβ) elevation and deposition in the brain. However, the etiology of the sporadic form of AD—accounting for 95% of the remaining cases—is still unknown, and no effective therapy for AD is available. As result, the AD research field has moved drastically toward prevention and away from treatment, leaving millions of patients worldwide with little hope for a new effective drug. For this reason, it is extremely important to identify new targets that could potentially offer novel therapeutic opportunities with real disease-modifying capacity. 12/15-Lipoxygenase (12/15-LO) is an enzyme that is widely expressed in the central nervous system where it catalyzes the conversion of arachidonic 1400w mg to 12-hydroxyeicosatetranoic acid (12-HETE) and 15-hydroxyeicosatetranoic acid in different proportions (, ). Its protein levels and enzymatic activity are significantly elevated in patients with AD and those with a clinical diagnosis of mild cognitive impairment, suggesting an early involvement of the pathway in AD pathogenesis (, ). In addition, genetic absence or the early pharmacological blockade of 12/15-LO prevents cognitive impairment and the development of AD-like neuropathology in transgenic mouse models of the disease (). However, whether the 12/15-LO pharmacological blockade is beneficial after the pathological phenotype of the disease has developed remains unknown. The aim of this study was to investigate the effect of 12/15-LO pharmacological inhibition on the AD-like phenotype of triple transgenic (3xTg) mice receiving the treatment starting at 12 months of age. After 3 months, compared with controls, animals treated with 6,11-dihydro-5-thia-11-aza-benzo[a]-fluorene (PD146176), a specific and selective 12/15-LO noncompetitive inhibitor (, , ), had a reversal of their memory and learning deficits, reduced Aβ and tau neuropathology, and improved synaptic integrity. In vivo and in vitro studies showed that 12/15-LO pharmacological inhibition–mediated biological effects were caused by a direct modulatory action of this pathway on autophagy. Methods and Materials
    Results
    Discussion Previously, we have shown that 12/15-LO expression levels modulated the development of AD-like amyloidosis in a transgenic APP mouse model, and the early pharmacological blockade of 12/15-LO enzymatic activation was effective in preventing memory decline, brain amyloidosis, and tau phosphorylation in 3xTg mice (17, 18). However, to prove that this approach has potential translational value in a real-life scenario, its efficacy against AD after the pathology is established remained to be shown. With this goal in mind, we designed the current study, in which 3xTg mice were treated with a 12/15-LO inhibitor starting at 12 months of age, after they have developed the full AD-like phenotype characterized by cognitive decline and amyloid and tau neuropathology (19). Three months later, while untreated 3xTg had memory and learning impairments, the behavioral response of the treated mice was undistinguishable from the WT group in the cued phase of the fear conditioning test. This result suggests that pharmacological blockade of 12/15-LO enzyme induced a functional restoration of the behavioral impairments in the aged mice. However, no changes were detected in the contextual phase of the fear conditioning paradigm. This discrepancy could be explained by the different cognitive functions and brain areas assessed by the two phases. In particular, the cued phase measures the ability to associate an unpleasant stimulus (i.e., foot shock) with a neuronal conditioned stimulus (i.e., sound) and requires both amygdala and hippocampal contribution. By contrast, the contextual phase measures the ability to associate the unpleasant stimulus with the environment where it happens and requires hippocampal contribution only (20).