FIGURE 11.

Proposed mechanism by which Dyrk1A activation by Ca²⁺/calpain I contributes to neurofibrillary pathology in AD brain. Intraneuronal calcium is increased due to excitotoxicity, β-amyloid neurotoxicity, and free radical injury and activates calpain I, which proteolyzes Dyrk1A and in turn activates it. Activated Dyrk1A phosphorylates SC35 and ASF/SF2 and suppresses their facilitation in Tau exon 10 inclusion, resulting in an increased ratio of 3R-Tau/4R-Tau. Activated Dyrk1A also phosphorylates Tau and makes it a more favorable substrate for GSK-3β as well as promoting Tau exon 10 exclusion. All of these changes lead to abnormal hyperphosphorylation of Tau and finally neurofibrillary pathology.