Background: Abnormal hyperphosphorylation of the microtubule-associated protein Tau is a hallmark of Alzheimer disease. Results: Acidosis of the brain activates and translocates asparaginyl endopeptidase from neuronal lysosomes to the cytoplasm where it leads to Tau hyperphosphorylation by inhibition of protein phosphatase 2A through cleavage of its inhibitor 2 into two active fragments. Conclusion: Activated asparaginyl endopeptidase causes Tau pathology. Significance: Brain acidosis can trigger Tau hyperphosphorylation.

Truncations of tau protein at aspartic acid421 (D421) and glutamic acid391 (E391) residues are associated with neurofibrillary tangles (NFTs) in the brains of Alzheimer disease (AD) patients. Using immunohistochemistry with antibodies to D421- and E391-truncated tau (Tau-C3 and MN423, respectively), we correlated the presence of NFTs composed of these truncated tau proteins with clinical and neuropathologic parameters in 17 AD and 23 non-AD control brains. The densities of NFTs composed of D421- or E391-truncated tau correlated with clinical dementia index and Braak staging in AD. Glutamic acid391 tau truncation was prominent in the entorhinal cortex, whereas D421 truncation was prominent in the subiculum, suggesting that NFTs composed of either D421- or E391-truncated tau may be formed mutually exclusively in these areas. Both truncations were associated with the prevalence of the apolipoprotein E epsilon4 allele. By double labeling, intact tau in NFTs was commonly associated with D421-cleaved tau but not with E391-truncated tau; D421-cleaved tau was never associated with E391-truncated tau. These results indicate that tau is not randomly proteolyzed at different domains, and that proteolysis occurs sequentially from the C-terminus to inner regions of tau in AD progression. Identification of NFTs composed of tau at different stages of truncation may facilitate assessment of neurofibrillary pathology in AD.

Phosphorylation, cleavage and conformational changes in tau protein all play pivotal roles during Alzheimer's disease (AD). In an effort to determine the chronological sequence of these changes, in this study, using confocal microscopy, we compared phosphorylation at several sites (Ser(199/202/396/404/422)-Thr(205) and the second repeat domain), cleavage of tau (D(421)) and the canonical conformational Alz-50 epitope. While all of these posttranslational modifications are found in neurofibrillary tangles (NFTs) at all stages of the disease, we found significantly higher numbers of phospho-tau positive NFTs when compared with cleaved tau (P = 0.006 in Braak III; P = 0.002 in Braak IV; P = 0.012 in Braak V) or compared with the Alz-50 epitope (P < 0.05). Consistent with these findings, in a double transgenic mice model (Tet/GSK-3beta/VLW) overexpressing the enzyme glycogen synthase kinase-3beta (GSK-3beta) and tau with a triple FTDP-17 mutation (VLW) with AD-like neurodegeneration, phosphorylation at sites Ser(199/202)-Thr(205) was greater than truncated tau. Taken together, these data strongly support the notion that the conformational changes and truncation of tau occur after the phosphorylation of tau. We propose two probable pathways for the pathological processing of tau protein during AD, either phosphorylation and cleavage of tau followed by the Alz-50 conformational change or phosphorylation followed by the conformational change and cleavage as the last step.

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Alzheimer's disease (AD) is multifactorial and, to date, no single cause of the sporadic form of this disease, which accounts for over 99% of the cases, has been established. In AD brain, protein phosphatase-2A (PP2A) activity is known to be compromised due to the cleavage and translocation of its potent endogenous inhibitor, normalI2PP2A, from the neuronal nucleus to the cytoplasm. Here, we show that adeno-associated virus vector-induced expression of the N-terminal I2NTF and C-terminal I2CTF halves of normalI2PP2A, also called SET, in brain reproduced key features of AD in Wistar rats. The I2NTF–CTF rats showed a decrease in brain PP2A activity, abnormal hyperphosphorylation and aggregation of tau, a loss of neuronal plasticity and impairment in spatial reference and working memories. To test whether early pharmacologic intervention with a neurotrophic molecule could rescue neurodegeneration and behavioral deficits, 2.5-month-old I2NTF–CTF rats and control littermates were treated for 40 days with Peptide 6, an 11-mer peptide corresponding to an active region of the ciliary neurotrophic factor. Peripheral administration of Peptide 6 rescued neurodegeneration and cognitive deficit in I2NTF–CTF animals by increasing dentate gyrus neurogenesis and mRNA level of brain derived neurotrophic factor. Moreover, Peptide 6-treated I2NTF–CTF rats showed a significant increase in dendritic and synaptic density as reflected by increased expression of synapsin I, synaptophysin and MAP2, especially in the pyramidal neurons of CA1 and CA3 of the hippocampus.

Amyloid plaques and neurofibrillary tangles are the hallmarks of Alzheimer's disease and have been the focus of disease etiology and pathogenesis. However, in the larger picture of a complex disease, the precise etiology of the lesions per se, as well as the clinical disease, remain to be defined. In this regard, to date no single process has been identified as a useful target and treatment efforts have shown no meaningful progress. Therefore, alternative ideas that may lead to new and effective treatment options are much needed. KeywordsAlzheimer's disease; amyloid; fibrillary deposits; oxidative stress; tau Amyloid plaques and neurofibrillary tangles (NFTs) are pathological hallmarks of the progression of Alzheimer's disease (AD). The questions of how, why and when they appear are, therefore, pertinent to understanding the disorder and, as a result, research efforts into the relationship between lesion and pathogenesis have been substantial. It is now known that specific molecular events are associated with the development of AD, although their exact relationship to lesion appearance is still controversial. Pathogenic mutations leading, for example, to amyloid-β (Aβ) deposition, are a primary piece of evidence [1][2][3], while a wide range of other metabolic abnormalities have been proposed [4][5][6][7][8]. During early AD stages, cell cycle deregulation has been related to the disease [9,10], which may also contribute to the protein aggregates. Other processes, such as oxidative damage to DNA and RNA, have † Author for correspondence: Tel.: +1 216 368 3670 Fax: +1 216 368 8964 mark.smith@case.edu.For reprint orders, please contact reprints@expert-reviews.com Financial & competing interests disclosureThis work was funded by NIH grant AG026151. Mark A Smith is, or has in the past been, a paid consultant for, owns equity or stock options in and/or receives grant funding from Anavex, Canopus BioPharma, Medivation, Neurotez, Neuropharm, Panacea Pharmaceuticals and Voyager Pharmaceuticals. George Perry is, or has in the past been, a paid consultant for and/or owns equity or stock options in Neurotez Pharmaceuticals, Panacea Pharmaceuticals, Takeda Pharmaceuticals and Voyager Pharmaceuticals. Xiongwei Zhu is a paid Advisory Board member for Medivation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Genetic events: causative, but how? NIH Public AccessPathogenic mutations leading to familial autosomal-dominant AD involve the Aβ precursor protein (APP) gene [22,23], and presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes [24]. Apolipoprotein E (APOE) polymorphisms, sometimes referred to as familial late-onset AD, are not mutations per se, but are a significant predisposing factor [25,26]. In particular, the APOE gene has three isoforms (ε2,...

Background: In Alzheimer brain, I 2 PP2A is translocated from the neuronal nucleus to the cytoplasm and promotes abnormal hyperphosphorylation of Tau. Results: Inactivation of nuclear localization signal (NLS) causes retention of I 2 PP2A in the cell cytoplasm, where it promotes Tau hyperphosphorylation by affecting PP2A signaling. Conclusion: Retention of I 2 PP2A in cell cytoplasm results in Tau hyperphosphorylation. Significance: The study provides potential tools for investigating Tau-based therapeutics.

A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT) provides protection in a rat model for Alzheimer’s disease (AD). In this model, viral expression of the phosphoprotein phosphatase 2A (PP2A) endogenous inhibitor, the I2PP2A or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic β-amyloid protein. Dietary supplementation with EHT for 6–12 months resulted in substantial amelioration of all of these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiological studies indicating the coffee drinkers have substantially lowered risk of developing AD.