Tau is a microtubule-stabilizing protein detected in both cytosolic/cytoskeletal and nuclear cellular compartments of neuronal and non-neuronal cells, with a tightly regulated phosphorylation, in physiology (mitosis for example) and pathology (neurofibrillary tangles). In Alzheimer’s disease (AD) it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration. The amyloid β-precursor protein (AβPP) is considered pivotal in the genesis of AD, and the “amyloid hypothesis” states that amyloid β-peptides (Aβ), derived from aberrant AβPP processing, cause neurodegeneration and tau hyperphosphorylation. Here we provide evidence that AβPP, when ectopically overexpressed or in cells bearing trisomy 21, modulates the phosphorylation of tau in mitotic and pathogenic phosphoepitopes during cell cycle and regulates the intracellular localization of phospho-tau, reducing the nuclear pool and the overall ratio nuclear/cytoskeletal. We show that the modulation of tau phosphorylation mediated by AβPP is strictly dependent on β-secretase activity as well. This specific phosphorylation of tau is required during mitosis in vitro and in vivo, likely via an ERK1/2 signaling cascade; the consequent phenotype is an upregulation of cell growth kinetic induced by AβPP in proliferating cell lines. Also in differentiated neuronal A1 cells, the overexpression of AβPP modulates tau phosphorylation, altering the ratio between cytoskeletal and nuclear pools, but in this case AβPP induces cell death. The nuclear localization of phospho-tau is significantly underrepresented in neurons of AD patients, in which predominate neurofibrillary tangles, in comparison to non-AD patients. Finally we investigate the potential protective effect of sodium selenate on tau phosphorylation and tau inclusions in a transgenic mouse model of human tauopathy. Treatment with sodium selenate in these transgenic mice reduces both phospho-tau and tau inclusions, likely by activating phosphatase activity (PP2A) and increasing the autophagic degradation of tau aggregates. In summary, in this work we provide evidence for a direct contribution of APP in a signaling activity targeted to the activation of specific kinases, with a role in the phosphorylation and homeostasis of the nuclear and the cytoskeletal pool of tau, with consequences in cell cycle dynamics that may lead to cell death in postmitotic neurons. The use of pharmacological tools that may reduce kinases’ activation and stimulate the autophagic degradation of tau inclusions, as shown here using Na Selenate in transgenic mice, may revert this pathological process. In our opinion a deeper comprehension of molecular mechanisms that cause the disequilibrium between nuclear vs cytoskeletal phosphorylation of tau is essential for the identification of novel targets for AD therapy.
|Titolo:||Tau nucleare: un possibile nuovo target per la terapia della malattia di Alzheimer|
|Altri titoli:||Nuclear tau: a possible novel target for Alzheimer's disease therapy|
|Parole chiave:||Aggregati neurofibrillari|
|Data di pubblicazione:||24-apr-2013|
|Appare nelle tipologie:||8.2 Tesi di dottorato (Ex-ROAD)|