PubMed: 26751493

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.
Babić Leko M | Bažadona D | Buée L | Delalle I | Di Giovanni G | Harrington C | Hof PR | Jovanov-Milošević N | Wischik C | Wray S | de Silva R | Šimić G

Evidence 2803807135

MB is a phenothiazine that crosses the blood brain barrier and acts as a redox cycler. Moreover, besides its beneficial properties as being able to improve energy metabolism and to act as an antioxidant, it is also able to reduce tau protein aggregation

Evidence 7ed5a88805

The projection domain of tau may be involved in cell signaling that occurs through the interaction with Lck, Fgr and cSrc (Src-family kinases), growth factor receptor-bound protein 2 (Grb2), phospholipase C- [70], phosphatidylinositol and phosphatidylinositol bisphosphate [71,72], peptidyl-prolyl cis/trans isomerase Pin 1, and many others (for review see [73]), making them potential therapeutic targets in tauopathies [74].

Evidence 90058801dd

Green coffee, a non-toxic small molecule, found to be an inhibitor of protein phosphatase 2A methylesterase, was shown to improve cognitive and motor performance in mouse models with tau pathology

Evidence e3607587ab

Other possible inhibitors of tau aggregation are rhodanine-based inhibitors, phenylthiazolyl-hydrazide inhibitors, N-phenylamines, phenothiazines and benzothiazoles, and polyphenols and anthraquinones

Evidence e2272b4168

In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appea rs that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171].

Evidence 8f48420908

A quite different strategy is to target tau clearance—e.g., by rapamycin that induces macroautophagy [175], inhibitors of Hsp90 chaperone protein that binds to misfolded proteins or by immunotherapeutic approaches [176].

Evidence f744c3df66

In a prospective study three different synaptic protein (synaptophysin, SNAP-25 and syntaxin) were found to be progressively decreased in neocortex at Braak stages III-VI [158], NFT-bearing neurons demonstrating, for example, a 35%–57% reduction in synaptophysin mRNA in AD brain [159].

Evidence 9c5619cec8

The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167].

Evidence fa384ad7e8

In synapses, the projection domain of tau interacts with protein kinase Fyn (plays an important role during myelination [75]), postsynaptic density protein 95 (PSD-95) [76], and N-methyl-D-aspartate receptors (NMDAR).

Evidence a932e25429

An additional “knot” of tau being entangled in epigenetic landscape of neurodegeneration comes from the finding that by acting as a HDAC6 inhibitor, tau is being indirectly involved in both (dys)regulation of transcriptional activity and impairment of autophagic clearance by the ubiquitin proteasome system [81,82].

Evidence a9d4e49d65

Recently, it has been proposed that tau protein acetylation may be responsible for tau aggregation in AD. Grinberg and collaborators detected tau acetylation at Lys274 in all tauopathies (both primary and secondary), except in AgD

Evidence bf04def8d1

A PSEN1 mutation causes a Pick’s disease phenotype including FTD tau pathology without deposition of Abeta [145]; some MAPT single nucleotide polymorphisms have also been linked to sporadic Parkinson’s disease (PD, [146]);

Evidence a3ed983aea

Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the

Evidence b241e7a607

On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).

Evidence 910934d579

The tau fragment first isolated from the PHF core is approximately 100 amino acids in length. Its N-terminus was defined by sequence analysis [30,56], and its C-terminus was defined by epitope mapping of MN423. Immunoreactivity was shown to depend on a specific C-terminal trunctation at Glu391 [33,150].

Evidence a75c7a9450

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.

Evidence ea1c8b37f5

Poorkaj et al. reported two exonic mutations (P301L and V337M) in two families with FTDP-17 [139], while Hutton et al. reported six different mutations in 10 families: three of these mutations (G272V, P301L and R406W) were missense mutations in exons, while the other three were in the 5' splice site of exon 10 [140].


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