Figure 2: Schematic view of relations between amyloid and Tau in Alzheimer’s disease. The interpretation hinges on the concept that the production of the Tau-P* intermediates are the central molecular species in the overall process. The incorporation of GSK3 as a major coupling link between the two pathologies is underscored essentially by in vivo observations in the mono- and bigenic mouse models discussed in the text. Protein Tau is a very soluble, naturally unfolded protein that in physiological conditions is located mainly in axons and attached to microtubules, denoted as Tau-MT. Activation by amyloid of both GSK3 kinases, together with other kinases including Mar2/Par1, gradually transforms Tau-MT into a pool of soluble, phosphorylated Tau (pTau) in the cytoplasm. Because of their delocalization, the pTau species undergo further posttranslational modifications, mainly including additional phosphorylation but eventually also nitrosylation, acetylation, truncation, all causing the transition into the conformational protein Tau species that we previously denoted as Tau-P* [11]. This as yet molecularly undefined intermediate likely represents soluble low-order aggregates that cause the early synaptic defects and cognitive problems typical for all tauopathies, with brain-region specificity as discussed in the text. The escape of Tau-P* from normal elimination via the proteasome and/or by autophagy leads to its accumulation, which by mass-action results in aggregation into NFT. We primarily consider NFT not to be detrimental for neurons, and initially they can even constitute a relative safety measure, as they reduce the free levels of Tau-P* and thereby its negative actions. Conversely, in the long term, the progressive accumulation of Tau-P* into more NFT deposition in neuropil and soma must invoke negative effects and eventually result in axonal and dendritic defects that culminate in neurodegeneration. This process is schematically reflected by the green-to-red color gradient of the background of the NFT box in the scheme.