Uman-derived seeds even at the concentration, which was adequate for total depletion of tau seeds from P301S transgenic model (300 nM) [331]. Beta-glucuronidase/GUSB Protein Others Similarly, two tested N-terminal antibodies (aa15-24, aa 25-30) and MC1 (which recognises both N-terminus and microtubule binding domain) failed to completely prevent seeding of AD tau in a seeded aggregation cell model [67] and in vivo [8]. In contrast, Nobuhara and colleagues [240] demonstrated that N-terminal antibody C13 (aa2-18) efficiently removed tau from rTg4510 brain extracts and human AD high molecular weight tau (HMW). Additionally, the antibody lowered tau uptake of pathological mouse and human AD HMW tau Amphiregulin Protein HEK 293 within a sensitive FRET-based in mouse major neurons. It can be significant to note that the antibodies targeting the N-terminus on tau are usually not specific to diseased tau, and they possibly reduce the amount of physiological tau. Although valuable effects of N-terminal antibodies on reduction of tau uptake or inhibition of seeding activity are nonetheless a matter of discussion, the development of novel therapeutic tau antibodies has shifted for the mid domain of tau protein. Inside the mid region, phosphorylation of tau in the position pS202 and pT205 was reported as an intracellular and extracellular marker for tau pathology in AD [39], and is potentially involved in neuronal apoptosis [166]. Moreover, phosphorylation of tau at T231 was also reported as an early event in AD [207, 208]. Numerous mid-domain tau antibodies (PT51, aa153-158, PT79, aa131-140, PT89, aa173-178) demonstrated comprehensive depletion of mouse transgenic tau P301S-derived tau seeds. However, incomplete depletion of human derived seeds even at maximal concentration of 300 nM [331], suggests the distinctive composition of mouse and human tau seeds. However, the antibody 6C5 (aa125-131) efficiently removed tau ( 85 reduction) from each mouse transgenic (Tg4510) brain extracts and human AD HMW tau (82 reduction). In addition, the antibody was the most productive in reducing tau uptake of pathological mouse tau ( 90 reduction) and human AD HMW tau ( 75 reduction) at the same time within a sensitive FRET-based assay in mouse main neurons [240]. Similarly, the antibody recognising aa235-250, completely neutralised seeding activity of AD and PSP tau in a seeded aggregation cell model with an IC50 of two.9 nM and 5.6 nM, respectively [67]. These final results demonstrate that antibodies recognising the mid region of tau might be successful within the reduction of tau uptake and neutralisation of tau seeding activity. In contrast to in vitro experiments, research applying tau antibodies raised against this region of tau showed inconsistent final results in preclinical in vivo experiments [72, 73, 342]. The third class of antibodies target the microtubule binding region (MTBR), which plays a vital role in polymerization and stability of microtubules [36, 168,328]. Alternatively, this region is accountable for the pathological tau-tau interaction. It was reported that the C-terminal fragments were far more prone to filament formation than the N-terminal sequences [257, 258]. Particularly, the area spanning aa244-372 corresponds towards the amyloid-forming region on tau protein [315]. This home is attributed towards the hexapeptide sequence 306VQIVYK311 on the 2nd repeat of MTBR which was shown to promote tau aggregation by a nucleation dependent mechanism [338]. Current cryo-electron microscopy study demonstrated that this hexapeptide packed through a heterotypic, non-staggered interfa.