The role of microtubule-associated protein Tau in neurodegeneration has been extensively investigated since the discovery of Tau amyloid aggregates in the brains of patients with Alzheimer's disease (AD). The process of formation of amyloid fibrils is known as amyloidogenesis and attracts much attention as a potential target in the prevention and treatment of neurodegenerative conditions linked to protein aggregation. Cerebral deposition of amyloid aggregates of Tau is observed not only in AD but also in numerous other tauopathies and prion diseases. Amyloidogenesis of intrinsically unstructured monomers of Tau can be triggered by mutations in the Tau gene, post-translational modifications, or interactions with polyanionic molecules and aggregation-prone proteins/peptides. The self-assembly of amyloid fibrils of Tau shares a number of characteristic features with amyloidogenesis of other proteins involved in neurodegenerative diseases. For example, in vitro experiments have demonstrated that the nucleation phase, which is the rate-limiting stage of Tau amyloidogenesis, is shortened in the presence of fragmented preformed Tau fibrils acting as aggregation templates ("seeds"). Accordingly, Tau aggregates released by tauopathy-affected neurons can spread the neurodegenerative process in the brain through a prion-like mechanism, originally described for the pathogenic form of prion protein. Moreover, Tau has been shown to form amyloid strains-structurally diverse self-propagating aggregates of potentially various pathological effects, resembling in this respect prion strains. Here, we review the current literature on Tau aggregation and discuss mechanisms of propagation of Tau amyloid in the light of the prion-like paradigm.

Amyloid aggregates of Tau protein have been implicated in etiology of many neurodegenerative disorders including Alzheimer's disease (AD). When amyloid growth is induced by seeding with preformed fibrils assembled from the same protein, structural characteristics of the seed are usually imprinted in daughter generations of fibrils. This so-called conformational memory effect may be compromised when the seeding involves proteins with non-identical sequences leading to the emergence of distinct structural variants of fibrils (amyloid ‘strains’). Here, we investigate cross-seeding of full-length human Tau (FL Tau) with fibrils assembled from K18 and K18ΔK280 fragments of Tau in the presence of poly-L-glutamate (poly-Glu) as an enhancer of Tau aggregation. To study cross-seeding between Tau polypeptides and the role of the conformational memory effect in induction of Tau amyloid polymorphism, kinetic assays, transmission electron microscopy, infrared spectroscopy and limited proteolysis have been employed. The fastest fibrillization was observed for FL Tau monomers seeded with preformed K18 amyloid yielding daughter fibrils with unique trypsin digestion patterns. Morphological features of daughter FL Tau fibrils induced by K18 and K18ΔK280 seeds were reminiscent of the mother fibrils (i.e. straight paired fibrils and paired helical filaments (PHFs), respectively) but disappeared in the following generations which became similar to unpaired FL Tau amyloid fibrils formed de novo. The structural evolution observed in our study was accompanied by disappearance of the unique proteolysis profile originated from K18. Our findings may have implications for understanding molecular mechanisms of the emergence and stability of Tau amyloid strains.

Analysis of the main triterpenoid profile of chloroform-soluble cuticular waxes of heather flowers and leaves by GC-MS revealed the following composition: five triterpene acids - betulinic, oleanolic, ursolic, 3-oxo-olean-12-en-28-oic and 3-oxo-ursan-12-en-28-oic; eight monohydroxyalcohols - α-amyrin, β-amyrin, cycloartanol, 24-methylenecycloartanol, friedelinol, germanicol, lupeol and taraxasterol; three dihydroxyalcohols - betulin, erythrodiol and uvaol; two aldehydes - oleanolic and ursolic; four ketones - α-amyrenone, 4-epi-friedelin, friedelin and taraxerone and seven steroids - campesterol, cholesterol, sitostanol, sitosterol, stigmasterol, stigmasta-3,5-dien-7-one and stigmastane-3,6-dione. Triterpenoids accounted for 20% and 65% by mass of flower and leaf waxes, respectively, which suggest that heather leaves represent a very promising source of these compounds. Ursolic acid was the principal triterpenoid in the cuticular wax of both organs, whereas among the neutral triterpenes, friedelin and uvaol were the most abundant in flowers and leaves, respectively. This report provides the first thorough overview of the triterpenoid composition of cuticular waxes of heather.