Geon Alzheimer's Disease: The Role of Tau's
Phosphatase-Activating Domain in Pathology Spreading



Understanding the mechanism of pathology spreading in Alzheimer's disease (AD) is essential for guiding therapeutic strategies. The failure of Tau aggregation inhibitors indicates that Tau aggregates may not play a critical role. Recently, the phosphatase-activating domain (PAD) of Tau has emerged as a central player in pathology spreading. PAD has the capacity to activate protein phosphatase 1 (PP1), which in turn activates glycogen synthase kinase-3 (GSK-3). In addition to the well known function of GSK-3 as a Tau kinase, GSK-3 can also enhance neuronal excitability. In a normal free Tau, the "paper-clip conformation" prevents PAD from interacting with PP1. In pathological Tau (phosphorylated and/or truncated), PAD becomes exposed, capable of activating the PP1/GSK-3/hyperexcitability pathway. According to the BDNF Cascade Hypothesis presented in previous papers, AD is fundamentally caused by calcium overload, which in turn arises from hyperexcitability. Therefore, the pathology spreading between neurons could result from "hyperexcitability transfer" mediated by PAD exposure in pathological Tau proteins, whether they are monomeric or aggregated. On the basis of this spreading mechanism, therapeutic development should target PAD exposure (e.g., by PAD antibody), rather than Tau aggregation.


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