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• W2965213848 abstract "DM is a major metabolic disorder that may result in neurodegeneration. Disrupted insulin signaling pathway or glucose metabolism deficiency can induce τ hyperphosphorylation. τ is a microtubule-associated protein. It is moderately phosphorylated under physiological conditions but its hyperphosphorylation reflects pathogenicity and is a major pathological hallmark of neurodegeneration. Phosphorylated τ at Thr231 exists in the two distinct cis and trans conformations. cis p-τ is neurotoxic and drives neurodegeneration. cis p-τ is accumulated in cultured neurons upon oxidative stress as well as nutrition depletion. Several conditions result in neurodegeneration; among which diabetes mellitus (DM) is of crucial importance. Tau (τ) malfunction is a major pathological process participating in neurodegeneration. Despite extensive considerations, the actual causative link between DM and τ abnormalities remains uncertain thus far. Phosphorylated (p)-τ at Thr–Pro motifs can exist in the two distinct cis and trans conformations. cis is neurotoxic, and is accumulated upon various stress conditions, such as nutrition depletion. We assume that pathogenic cis p-τ is the central mediator of neurodegeneration in DM, and propose why different brain areas give various responses to stress conditions. We herein juxtapose recent approaches in diabetic neurodegeneration and propose a therapeutic target to stop neuronal loss during DM. Several conditions result in neurodegeneration; among which diabetes mellitus (DM) is of crucial importance. Tau (τ) malfunction is a major pathological process participating in neurodegeneration. Despite extensive considerations, the actual causative link between DM and τ abnormalities remains uncertain thus far. Phosphorylated (p)-τ at Thr–Pro motifs can exist in the two distinct cis and trans conformations. cis is neurotoxic, and is accumulated upon various stress conditions, such as nutrition depletion. We assume that pathogenic cis p-τ is the central mediator of neurodegeneration in DM, and propose why different brain areas give various responses to stress conditions. We herein juxtapose recent approaches in diabetic neurodegeneration and propose a therapeutic target to stop neuronal loss during DM. high glucose levels can induce nonenzymatic protein glycation, named AGEs. AGEs may have endogenous (inside the body) or exogenous (dietary) origin. AGE accumulation may result in different diabetic related complications; likely through oxidative stress and inflammation. AGEs may trigger different signaling pathways, through interaction with their specific receptors. amyloid precursor protein is a transmembrane protein, whose misprocessing reflects Aβ polypeptide formation. Aβ is one of the major pathological hallmarks accumulating in the extracellular matrix and forms Aβ plaques. Aβ plaques may additionally induce inflammation and oxidative stress, reflecting synapse disruption and neurodegeneration. GSK3β is a member of the proline directed serine–threonine kinase family playing a central role in insulin signaling pathway. It also phosphorylates τ protein. GSK3β function is controlled by phosphorylation at different sites. AKT is a major GSK3β inhibitor being activated upon disturbed insulin signaling pathway in different diseases, such as AD and DM. LTP/LTD are the two important synaptic activities, involved in learning and memory. LTP is a long-lasting synapse strengthens primarily identified in rat hippocampus. Disruption of LTP can induce different cognitive decline diseases; such as AD and PD. LTD is the opposite of LTP and can decrease persistent synapse strengthens. Pin1 is an enzyme that catalyzes cis/trans isomerization of serine/threonine–proline motifs. Pin1 has two distinct domains including the WW domain at the N terminus and PPIase domain at the C terminus. WW domain binds to specific serine/threonine–proline motifs on target proteins and the PPIase domain can induce cis/trans conformational changes in target proteins. Pin1 can affect localization, phosphorylation, interaction, stability, and activity of target proteins. Deregulation of Pin1 activity has contributed to different diseases such as AD, cancer, and DM. Pin1 plays different roles in the insulin signaling pathway. Pin1 can modulate the insulin signaling pathway by affecting activity of proteins such as AKT and GSK3β. Pin1 is suppressed differently under various stress conditions. It is phosphorylated at Ser71 upon traumatic brain injury, downregulated in AD, or oxidized at Cys113 upon oxidative stress; resulting in cis p-τ accumulation. τ is a microtubule-associated protein, whose function is to stabilize microtubule structure in axonal cytoskeleton. It is a phosphoprotein whose functions are thought to be controlled by phosphorylation but its abnormal hyperphosphorylation reflects pathogenicity. Abnormal τ hyperphosphorylation can induce τ dissociation from microtubules, resulting in its aggregation, NTF, and eventually neurodegeneration. There are over 80 phosphorylation sites on τ, and most of them are considered to be physiological sites. It has been demonstrated that phosphorylated τ at Thr–Pro domains may exist in the two distinct cis and trans conformations; whose conversion is mediated by Pin1 isomerase." @default.
• W2965213848 created "2019-08-13" @default.
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• W2965213848 date "2019-10-01" @default.
• W2965213848 modified "2023-09-26" @default.
• W2965213848 title "A Possible Neurodegeneration Mechanism Triggered by Diabetes" @default.
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• W2965213848 doi "https://doi.org/10.1016/j.tem.2019.07.012" @default.
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