Amyloid-beta Protein Precursor Regulates Phosphorylation and Cellular Compartmentalization of Microtubule Associated Protein Tau

Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When found hyperphosphorylated and aggregated in atrophic neurons, is considered the culprit for neuronal death in familial and sporadic tauopathies. In Alzheimer's disease (AD) it is instead debated whether entangled tau represents a cause or a consequence of the neurodegeneration. It is in fact unquestionably accepted the pivotal role of the amyloid- precursor protein (APP) in the genesis of the disease, and it is postulated that the formation of toxic amyloid-beta peptides (A) from APP is the primary event that subsequently induces abnormal tau phosphorylation. In this work we show that in the brain of AD patients there is an imbalance between the nuclear and the cytoskeletal pools of phospho-tau. We observed that in non-AD subjects there is a stable pool of phospho-tau which remains strictly confined to neuronal nuclei; while in AD patients the nuclear pool is significantly underrepresented in neurons bearing neurofibrillary tangles. A specific phosphorylation of tau seems required during mitosis in vitro and in vivo, likely via a Grb2-ERK1/2 signalling cascade; and in differentiated neuronal A1 cells the overexpression of APP modulates the phosphorylation of tau, altering the ratio between the cytoskeletal and the nuclear pools, and it correlates to cell death. Altogether our data provide the evidence that APP, beside amyloid formation, modulates also the phosphorylation of tau and its compartimentalization; an event that may lead to the formation of neurofibrillary tangles and to neurodegeneration when occurring in postmitotic neurons.