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    Summary: Inhibiting an enzyme that is elevated in people with Alzheimer’s appears to reverse cognitive decline and neuropathy associated with the disease.Source: Elsevier.Treatment with an inhibitor of 12/15-lipoxygenase, an enzyme elevated in patients with Alzheimer’s disease (AD), reverses cognitive decline and neuropathology in an AD mouse model, reports a new study in Biological Psychiatry. The effects were observed after the AD-like phenotype was already established in the mice, which is promising for its potential therapeutic use, as neuropathology tends to develop many years before the appearance of AD symptoms in patients.The study, by senior author Domenico Pratic and colleagues at Temple University in Philadelphia, Pennsylvania, offers some hope for a new treatment for patients with AD, who currently have no effective therapy options. Past research has focused on prevention of the disease by reducing the levels of proteins that cause brain plaques and tangles and kill nerve cells.

    “In this exciting new study, the authors provide support for a new experimental treatment approach that works by helping nerve cells digest toxic proteins that might otherwise cause cell death,” said John Krystal, Editor of Biological Psychiatry.

    First author Antonio Di Meco and colleagues used a triple transgenic (3xTg) mouse model that displays an AD-like phenotype, including cognitive decline, and Aβ and tau neuropathology characteristic of the disease in humans. They had already shown that early administration of the 12/15-lipoxygenase inhibitor PD146176 could prevent the onset of these features in mice. To achieve a more real-world scenario in this study, they waited until the transgenic mice were a year old, when both cognitive impairments and neuropathology were established, before administering the drug.

    “We show for the first time that selective pharmacologic inhibition of the 12/15-lipoxygenase enzyme rescues the entire AD-like phenotype,” Praticò said.

    Untreated 3xTg mice displayed impaired learning and memory as expected, but 3xTg mice that were administered PD146176 for 3 months were indistinguishable from normal mice in a memory test. In the same mice, the researchers found that PD146176 treatment significantly reduced the levels of Aβ and insoluble tau proteins.

    Inhibition of 12/15-lipoxygenase activated autophagy, the body’s natural kill system for cells. The activation was associated with decreased levels of tau, suggesting that the inhibitor works by re-activating the neuronal autophagy machinery to clear cellular buildup of tau.

     

    Inhibition of 12/15-lipoxygenase activated autophagy, the body’s natural kill system for cells. The activation was associated with decreased levels of tau, suggesting that the inhibitor works by re-activating the neuronal autophagy machinery to clear cellular buildup of tau. NeuroscienceNews.com image is for illustrative purposes only.

    The results indicate that pharmacological inhibition of 12/15-lipoxygenase reverses learning and memory impairments and reduces Aβ and tau neuropathology, even after their onset in aged mice.

    “Our findings have important translational value since they establish this protein enzyme as a novel and viable therapeutic target with real disease-modifying potential for AD,” Praticò said.

    ABOUT THIS ALZHEIMER’S DISEASE RESEARCH ARTICLE

    Source: Rhiannon Bugno –
    Image Source: NeuroscienceNews.com image is in the public domain.
    Original Research: for “12/15-Lipoxygenase Inhibition Reverses Cognitive Impairment, Brain Amyloidosis, and Tau Pathology by Antonio Di Meco, Jian-Guo Li, Benjamin E. Blass, Magid Abou-Gharbia, Elisabetta Lauretti, and Domenico Praticòc in Biological Psychiatry. Published online January 2017

    CITE THIS NEUROSCIENCENEWS.COM ARTICLE
    Elsevier “Mouse Model Points to Potential New Alzheimer’s Treatment.” NeuroscienceNews. NeuroscienceNews, 50 January 2017.
    <http://neurosciencenews.com/neurology-alzheimers-treatment-5872/>.

    Abstract

    12/15-Lipoxygenase Inhibition Reverses Cognitive Impairment, Brain Amyloidosis, and Tau Pathology by Stimulating Autophagy in Aged Triple Transgenic Mice

    Background
    The 12/15-lipoxygenase (12/15-LO) enzyme is upregulated in the brains of patients with Alzheimer’s disease (AD), and its expression levels influence the onset of the AD-like phenotype in mouse models. However, whether targeting this pathway after the neuropathology and behavioral impairments have been established remains to be investigated.

    Methods
    Triple transgenic (3xTg) mice received either PD146176—a selective and specific pharmacological inhibitor of 12/15-LO—or placebo starting at 12 months of age for 12 weeks. They were then assessed for the effect of the treatment on neuropathologies and behavioral impairments.

    Results
    At the end of the study, mice in the control group showed a worsening of memory and learning abilities, whereas mice receiving PD146176 were undistinguishable from wild-type mice. The same group also had significantly lower amyloid beta levels and deposition, less tau neuropathology, increased synaptic integrity, and autophagy activation. Ex vivo and in vitro genetic and pharmacological studies found that the mechanism involved in these effects was the activation of neuronal autophagy.

    Conclusions
    Our findings provide new insights into the disease-modifying action of 12/15-LO pharmacological inhibition and establish it as a viable therapeutic approach for patients with AD.

    “12/15-Lipoxygenase Inhibition Reverses Cognitive Impairment, Brain Amyloidosis, and Tau Pathology by Antonio Di Meco, Jian-Guo Li, Benjamin E. Blass, Magid Abou-Gharbia, Elisabetta Lauretti, and Domenico Praticòc in Biological Psychiatry. Published online January 2017 doi:10.1016/j.biopsych.2016.05.023

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