Alzheimer’s disease and green tea: Epigallocatechin-3-Gallate as a modulator of inflammation and oxidative stress

Alzheimer’s disease (AD) is the most common cause of dementia, characterised by a marked decline of both memory and cognition, along with pathophysiological hallmarks including amyloid beta peptide (Aβ) accumulation, tau protein hyperphosphorylation, neuronal loss and inflammation in the brain. Additionally, oxidative stress caused by an imbalance between free radicals and antioxidants is considered one of the main risk factors for AD, since it can result in protein, lipid and nucleic acid damage and exacerbate Aβ and tau pathology. To date, there is a lack of successful pharmacological approaches to cure or even ameliorate the terrible impact of this disease. Due to this, dietary compounds with antioxidative and anti-inflammatory properties acquire special relevance as potential therapeutic agents. In this context, green tea, and its main bioactive compound, epigallocatechin-3-gallate (EGCG), have been targeted as a plausible option for the modulation of AD. Specifically, EGCG acts as an antioxidant by regulating inflammatory processes involved in neurodegeneration such as ferroptosis and microglia-induced cytotoxicity and by inducing signalling pathways related to neuronal survival. Furthermore, it reduces tau hyperphosphorylation and aggregation and promotes the non-amyloidogenic route of APP processing, thus preventing the formation of Aβ and its subsequent accumulation. Taken together, these results suggest that EGCG may be a suitable candidate in the search for potential therapeutic compounds for neurodegenerative disorders involving inflammation and oxidative stress, including Alzheimer’s diseas

Mitophagy Failure in APP and Tau Overexpression Model of Alzheimer’s Disease.

Mitochondrial alterations and oxidative stress are common features of Alzheimer’s disease brain and peripheral tissues. Moreover, mitochondrial recycling process by autophagy has been found altered in the sporadic form of the disease. However, the contribution of the main proteins involved in this pathology such as amyloid- protein precursor (A PP) and tau needs to be achieved.With this aim, human unmodified fibroblasts were transduced with lentivectors encoding APP and Tau and treated with CCCP to study the mitophagy process. Both A PP and tau separately increased autophagy flux mainly by improving degradation phase. However, in the specific case of mitophagy, labeling of mitochondria by PINK1 and PARK2 to be degraded by autophagy seemed reduced, which correlates with the long-term accumulation of mitochondria. Nevertheless, the combination of tau and A PP was necessary to cause a mitophagy functional impairment reflected in the accumulation of depolarized mitochondria labeled by PINK1. The overexpression of Tau and APP recapitulates the mitophagy failure previously found in sporadic Alzheimer’s diseasepre-print3421 K

Tau Phosphorylation by GSK3 in Different Conditions

Almost a 20% of the residues of tau protein are phosphorylatable amino acids: serine, threonine, and tyrosine. In this paper we comment on the consequences for tau of being a phosphoprotein. We will focus on serine/threonine phosphorylation. It will be discussed that, depending on the modified residue in tau molecule, phosphorylation could be protective, in processes like hibernation, or toxic like in development of those diseases known as tauopathies, which are characterized by an hyperphosphorylation and aggregation of tau

Frontotemporal dementia-associated N279K tau mutation localizes at the nuclear compartment

Tau is a microtubule-associated protein that plays an important role in Alzheimer’s disease and related tauopathies. Approximately one-half of all cases of Frontotemporal dementia with parkinsonism-17 (FTDP-17) are caused by mutations in the MAPT gene. The N279K mutation is one of the three mutations more prevalent in FTDP-17 cases. Several studies have demonstrated that N279K Tau mutation alters alternative splicing inducing the presence of exon 10. Tau is mainly found in the cytosol of neuronal cells although it has also been localized within the nucleus. Here we demonstrate by biochemical and immunohistochemistry studies in COS-7 cells, that the proportion of mutant N279K Tau increases compared with wild-type at the cell nucleus although cell viability is not affected. These data will provide us with a better outline of the nuclear role of tau protein offering new clues related with this tauopathie.This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad; SAF-2014-53040-P (JA) and BFU2016-77885- P (FH)), the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII; JA)

Benefit of Oleuropein Aglycone for Alzheimer’s Disease by Promoting Autophagy

Alzheimer’s disease is a proteinopathy characterized by accumulation of hyperphosphorylated Tau and β-amyloid. Autophagy is a physiological process by which aggregated proteins and damaged organelles are eliminated through lysosomal digestion. Autophagy deficiency has been demonstrated in Alzheimer’s patients impairing effective elimination of aggregates and damaged mitochondria, leading to their accumulation, increasing their toxicity and oxidative stress. In the present study, we demonstrated by microarray analysis the downregulation of fundamental autophagy and mitophagy pathways in Alzheimer’s patients. The benefits of the Mediterranean diet on Alzheimer’s disease and cognitive impairment are well known, attributing this effect to several polyphenols, such as oleuropein aglycone (OLE), present in extra virgin olive oil. OLE is able to induce autophagy, achieving a decrease of aggregated proteins and a reduction of cognitive impairment in vivo. This effect is caused by the modulation of several pathways including the AMPK/mTOR axis and the activation of autophagy gene expression mediated by sirtuins and histone acetylation or EB transcription factor. We propose that supplementation of diet with extra virgin olive oil might have potential benefits for Alzheimer’s patients by the induction of autophagy by OLE

What’s in a gene? The outstanding diversity of MAPT

Tau protein is a microtubule-associated protein encoded by the MAPT gene that carries out a myriad of physiological functions and has been linked to certain pathologies collectively termed tauopathies, including Alzheimer’s disease, frontotemporal dementia, Huntington’s disease, progressive supranuclear palsy, etc. Alternative splicing is a physiological process by which cells generate several transcripts from one single gene and may in turn give rise to different proteins from the same gene. MAPT transcripts have been proven to be subjected to alternative splicing, generating six main isoforms in the central nervous system. Research throughout the years has demonstrated that the splicing landscape of the MAPT gene is far more complex than that, including at least exon skipping events, the use of 3′ and 5′ alternative splice sites and, as has been recently discovered, also intron retention. In addition, MAPT alternative splicing has been showed to be regulated spatially and developmentally, further evidencing the complexity of the gene’s splicing regulation. It is unclear what would drive the need for the existence of so many isoforms encoded by the same gene, but a wide range of functions have been ascribed to these Tau isoforms, both in physiology and pathology. In this review we offer a comprehensive up-to-date exploration of the mechanisms leading to the outstanding diversity of isoforms expressed from the MAPT gene and the functions in which such isoforms are involved, including their potential role in the onset and development of tauopathies such as Alzheimer’s diseaseThis research received no external fundin

A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer's disease.

Tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer's patients' brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer's disease and other tauopathies.This work was supported by the Ministerio de Ciencia, Innovación y Universidades from Spain (PGC2018-096177-B-00). Institutional grants from the Fundación Ramón Areces and Banco de Santander to CBMSO are also acknowledged. The Asociación Española Contra el Cáncer Scientific Foundation has financed Ricardo Gargini. We would like to acknowledge Daniela Rosiles for her technical support in cloning.S

Specific Peptide from the Novel W-Tau Isoform Inhibits Tau and Amyloid β Peptide Aggregation in Vitro

W-Tau, a new tau human-specific splicing isoform generated by intron retention, has been recently described. This isoform contains an 18-residue unique sequence corresponding to the translation of the retained region of intron 12. In this work, we have described that such 18-amino-acid peptide from the retained intron 12 can inhibit tau and β amyloid peptides aggregation under in vitro conditions. This inhibitory function is also present in smaller fragments of the 18-residue peptide.This research was funded by the Spanish Ministry of Science and Innovation (BES-2015-074405 and PGC2018-096177-BI00), the Center for Networked Biomedical Research on Neurodegenerative Diseases, and the Comunidad de Madrid (S2017/BMD). Institutional grants from the Fundación Ramón Areces and Banco de Santander are also acknowledged

Deconstructing mitochondrial dysfunction in Alzheimer disease

There is mounting evidence showing that mitochondrial damage plays an important role in Alzheimer disease. Increased oxygen species generation and deficient mitochondrial dynamic balance have been suggested to be the reason as well as the consequence of Alzheimer-related pathology. Mitochondrial damage has been related to amyloid-beta or tau pathology or to the presence of specific presenilin-1 mutations. The contribution of these factors to mitochondrial dysfunction is reviewed in this paper. Due to the relevance of mitochondrial alterations in Alzheimer disease, recent works have suggested the therapeutic potential of mitochondrial-targeted antioxidant. On the other hand, autophagy has been demonstrated to play a fundamental role in Alzheimerrelated protein stress, and increasing data shows that this pathway is altered in the disease. Moreover, mitochondrial alterations have been related to an insufficient clearance of dysfunctional mitochondria by autophagy. Consequently, different approaches for the removal of damaged mitochondria or to decrease the related oxidative stress in Alzheimer disease have been described. To understand the role of mitochondrial function in Alzheimer disease it is necessary to generate human cellular models which involve living neurons. We have summarized the novel protocols for the generation of neurons by reprogramming or direct transdifferentiation, which offer useful tools to achieve this result

Slower Dynamics and Aged Mitochondria in Sporadic Alzheimer’s Disease

Sporadic Alzheimer’s disease corresponds to 95% of cases whose origin is multifactorial and elusive. Mitochondrial dysfunction is a major feature of Alzheimer’s pathology, which might be one of the early events that trigger downstream principal events. Here, we show that multiple genes that control mitochondrial homeostasis, including fission and fusion, are downregulated in Alzheimer’s patients. Additionally, we demonstrate that some of these dysregulations, such as diminished DLP1 levels and its mitochondrial localization, as well as reduced STOML2 and MFN2 fusion protein levels, take place in fibroblasts from sporadic Alzheimer’s disease patients. The analysis of mitochondrial network disruption using CCCP indicates that the patients’ fibroblasts exhibit slower dynamics and mitochondrial membrane potential recovery. These defects lead to strong accumulation of aged mitochondria in Alzheimer’s fibroblasts. Accordingly, the analysis of autophagy and mitophagy involved genes in the patients demonstrates a downregulation indicating that the recycling mechanism of these aged mitochondria might be impaired. Our data reinforce the idea that mitochondrial dysfunction is one of the key early events of the disease intimately related with aging