It has been established for a long time that brain glucose metabolism is impaired in Alzheimer's disease. Recent studies have demonstrated that impaired brain glucose metabolism precedes the appearance of clinical symptoms, implying its active role in the development of Alzheimer's disease. However, the molecular mechanism by which this impairment contributes to the disease is not known. In this study, we demonstrated that protein O-GlcNAcylation, a common post-translational modification of nucleocytoplasmic proteins with beta-N-acetyl-glucosamine and a process regulated by glucose metabolism, was markedly decreased in Alzheimer's disease cerebrum. More importantly, the decrease in O-GlcNAc correlated negatively with phosphorylation at most phosphorylation sites of tau protein, which is known to play a crucial role in the neurofibrillary degeneration of Alzheimer's disease. We also found that hyperphosphorylated tau contained 4-fold less O-GlcNAc than non-hyperphosphorylated tau, demonstrating for the first time an inverse relationship between O-GlcNAcylation and phosphorylation of tau in the human brain. Downregulation of O-GlcNAcylation by knockdown of O-GlcNAc transferase with small hairpin RNA led to increased phosphorylation of tau in HEK-293 cells. Inhibition of the hexosamine biosynthesis pathway in rat brain resulted in decreased O-GlcNAcylation and increased phosphorylation of tau, which resembled changes of O-GlcNAcylation and phosphorylation of tau in rodent brains with decreased glucose metabolism induced by fasting, but not those in rat brains when protein phosphatase 2A was inhibited. Comparison of tau phosphorylation patterns under various conditions suggests that abnormal tau hyperphosphorylation in Alzheimer's disease brain may result from downregulation of both O-GlcNAcylation and protein phosphatase 2A. These findings suggest that impaired brain glucose metabolism leads to abnormal hyperphosphorylation of tau and neurofibrillary degeneration via downregulation of tau O-GlcNAcylation in Alzheimer's disease. Thus, restoration of brain tau O-GlcNAcylation and protein phosphatase 2A activity may offer promising therapeutic targets for treating Alzheimer's disease.

Ultra low-voltage low-power CMOS 4-2 and 5-2 compressors for fast arithmetic circuits Chang,

Neurofibrillary tangles of abnormally hyperphosphorylated tau is a hallmark of Alzheimer’s disease (AD) and related tauopathies. Tau is truncated at multiple sites by various proteases in AD brain. While many studies have reported the effect of truncation on the aggregation of tau, these studies mostly employed highly artificial conditions, using heparin sulfate or arachidonic acid to induce aggregation. Here, we report for the first time the pathological activities of various truncations of tau, including site-specific phosphorylation, self-aggregation, binding to hyperphosphorylated and oligomeric tau isolated from AD brain tissue (AD O-tau), and aggregation seeded by AD O-tau. We found that deletion of the first 150 or 230 amino acids (a.a.) enhanced tau’s site-specific phosphorylation, self-aggregation, and its binding to AD O-tau, and aggregation seeded by AD O-tau, but deletion of the first 50 a.a. did not produce a significant effect. Deletion of the last 50 a.a. was found to modulate tau’s site-specific phosphorylation, promote its self-aggregation, and cause it to be captured by and aggregation seeded by AD O-tau, whereas deletion of the last 20 a.a. had no such effects. Among the truncated taus, Tau151-391 showed the highest pathological activities. AD O-tau induced aggregation of Tau151-391 in vitro and in cultured cells. These findings suggest that the first 150 a.a and the last 50 a.a. protect tau from pathological characteristics and that their deletions facilitate pathological activities. Thus, inhibition of tau truncation may represent a potential therapeutic approach to suppress tau pathology in AD and related tauopathies.

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Background: Dysregulation of the alternative splicing of Tau exon 10 causes several types of neurodegenerative diseases. Results: SRp55 promotes Tau exon 10 inclusion. Dyrk1A interacts with SRp55, mainly phosphorylates its proline-rich domain and inhibits its ability to promote Tau exon 10 inclusion. Conclusion: Dyrk1A suppresses SRp55-promoted Tau exon 10 inclusion. Significance: Up-regulation of Dyrk1A disrupts the alternative splicing of Tau exon 10.

In the brains of individuals with Alzheimer's disease (AD) and chronic traumatic encephalopathy, tau pathology is accompanied usually by intracellular aggregation of transactive response DNA-binding protein 43 (TDP-43). However, the role of TDP-43 in tau pathogenesis is not understood. Here, we investigated the role of TDP-43 in tau expression in vitro and in vivo. We found that TDP-43 suppressed tau expression by promoting its mRNA instability through the UG repeats of its 3΄-untranslated region (3΄-UTR). The C-terminal region of TDP-43 was required for this function. Neurodegenerative diseases-causing TDP-43 mutations affected tau mRNA instability differentially, in that some promoted and others did not significantly affect tau mRNA instability. The expression levels of tau and TDP-43 were inverse in the frontal cortex and the cerebellum. Accompanied with cytoplasmic accumulation of TDP-43, tau expression was elevated in TDP-43M337V transgenic mouse brains. The level of TDP-43, which is decreased in AD brains, was found to correlate negatively with the tau level in human brain. Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. Down-regulation of TDP-43 may be involved in the tau pathology in AD and related neurodegenerative disorders.

Background: Dyrk1A regulates alternative splicing of exon 10 and phosphorylation of Tau. Results: Calpain I proteolyzes Dyrk1A and enhances its kinase activity, which promotes exon 10 exclusion and hyperphosphorylation of Tau. Conclusion: Truncation and activation of Dyrk1A may be responsible for Tau pathology in AD brains. Significance: These findings indicate a new mechanism linked to Tau pathology in AD.