Accumulating evident support intercellular transmission and subsequent amplification of pathological tau as a key mechanism for the progression of Alzheimer’s disease (AD) and other tauopathies. Blocking this transmission process is a promising therapeutic strategy to slow down disease progression. However, the molecular mechanisms that regulate pathological tau transmission remains largely unknown. Previous studies of tau transmission have been focused on pathological tau or the ‘seed’ itself. But, the amplification of pathological tau requires both the ‘seed’ and soluble tau, the ‘substrate’. What has generally been ignored is the potential effect of soluble tau on the amplification of pathological tau. Our preliminary study demonstrated that soluble α-synuclein (a-syn) post-translational modifications (PTMs) would dramatically affect the amplification of pathological a-syn, which highlights for the first time that PTMs on soluble protein would affect amplification of the corresponding pathological protein. Since many PTMs were identified on soluble tau, we hypothesize that soluble tau PTMs will also affect pathological tau amplification. Indeed, our preliminary data demonstrated that soluble tau acetylation could dramatically modulate the amplification of pathological tau prepared from AD brains (AD-tau). More interestingly, this effect is highly pathological tau conformation dependent. Pathological tau from corticobasal degeneration brains (CBD-tau) shows very different responses to soluble tau PTMs compared with AD-tau. Here, we propose to systematically explore how soluble tau PTMs would modulate the amplification of pathological tau in AD and other tauopathies. Firstly, PTMs on soluble tau from tauopathy brains has not been systematically identified and quantified. Therefore, we propose to systematically identify and quantify soluble tau PTMs in AD and other tauopathies by LC-MS/MS. Secondly, we will explore how soluble tau PTMs and PTM combinations would affect the amplification of pathological tau in AD and other tauopathies. Thirdly, the effects of soluble tau PTMs are highly pathological tau conformation dependent. Therefore, we propose to evaluate whether pathological tau in different disease subtypes, brain regions, and cell types (neurons and glial cells), would have different responses to soluble tau PTMs. Fourthly, it has been shown that different intracellular environment in neurons and glial cells would affect the amplification of pathological proteins. We propose to test whether different intracellular environment would also change the effect of soluble tau PTMs. Finally, the effects of soluble tau PTMs on AD-tau amplification will be evaluated in mouse. In summary, the proposed study represents the first to systematically explore how soluble tau PTMs would affect the amplification of pathological tau in AD and other tauopathies, which is a novel mechanism that modulates tau transmission. Successful performance of the proposed ...