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

Article type: Research Article

Authors: Nizzari, Mario^a | Barbieri, Federica^a | Gentile, Maria Teresa^b | Passarella, Daniela^c | Caorsi, Calentina^{d; e} | Diaspro, Alberto^d | Taglialatela, Maurizio^c | Pagano, Aldo^{a; f} | Colucci-D'Amato, Luca^b | Florio, Tullio^a | Russo, Claudio^{c; *}

Affiliations: [a] Dipartimento di Oncologia, Biologia e Genetica, Università degli Studi di Genova, Genova, Italy | [b] Dipartimento di Scienze della Vita, II Università di Napoli, Caserta; Istituto di Genetica e Biofisica “A. Buzzati-Traverso”, CNR, Napoli, Italy | [c] Dipartimento di Scienze per la Salute, Università degli Studi del Molise, Campobasso, Italy | [d] Dipartimento di Nanofisica, Istituto Italiano di Tecnologia-IIT, Dipartimento di Fisica, Università degli Studi di Genova, Genova, Italy | [e] Molecular Medicine Section, NHLI, Imperial College London, London, UK | [f] Istituto Nazionale per la Ricerca sul Cancro (IST), Genova, Italy

Correspondence: [*] Correspondence to: Prof. Claudio Russo, Dept. of Health Sciences, University of Molise, Via F. De Sanctis, 86100 Campobasso, Italy. Tel.: +39 0874404891; Fax: +39 0874404710; E-mail: [email protected].

Abstract: Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When hyperphosphorylated and aggregated in atrophic neurons, tau is considered the culprit for neuronal death in familial and sporadic tauopathies. With regards to Alzheimer's disease (AD) pathogenesis, it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration. In fact, it is unquestionably accepted that amyloid-β protein precursor (AβPP) plays a pivotal role in the genesis of the disease, and it is postulated that the formation of toxic amyloid-β peptides from AβPP 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 nuclear localization of phospho-tau is significantly underrepresented in neurons of AD patients bearing neurofibrillary tangles. A specific phosphorylation of tau is required during mitosis in vitro and in vivo, likely via a Grb2-ERK1/2 signaling cascade. In differentiated neuronal A1 cells, the overexpression of AβPP modulates tau phosphorylation, altering the ratio between cytoskeletal and nuclear pools, and correlates with cell death. Altogether our data provide evidence that AβPP, in addition to amyloid formation, modulates the phosphorylation of tau and its subcellular compartmentalization, an event that may lead to the formation of neurofibrillary tangles and to neurodegeneration when occurring in postmitotic neurons.

Keywords: Alzheimer disease, amyloid β-protein precursor, cell-cycle, tau protein

DOI: 10.3233/JAD-2011-101590

Journal: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 211-227, 2012