Amyloid-β protein precursor regulates phosphorylation and cellular compartmentalization of microtubule associated protein tau

Mario Nizzari, Federica Barbieri, Maria Teresa Gentile, Daniela Passarella, Calentina Caorsi, Alberto Diaspro, Maurizio Taglialatela, Aldo Pagano, Luca Colucci-D'Amato, Tullio Florio, Claudio Russo

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)211-227
Number of pages17
JournalJournal of Alzheimer's Disease
Volume29
Issue number1
DOIs
Publication statusPublished - 2012

Fingerprint

Microtubule-Associated Proteins
Amyloid beta-Protein Precursor
Phosphorylation
Alzheimer Disease
Neurofibrillary Tangles
Neurons
Amyloid
Tauopathies
Poisons
Brain Diseases
Mitosis
Cell Death
Peptides
Proteins

Keywords

  • Alzheimer disease
  • amyloid β-protein precursor
  • cell-cycle
  • tau protein

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

Cite this

Amyloid-β protein precursor regulates phosphorylation and cellular compartmentalization of microtubule associated protein tau. / Nizzari, Mario; Barbieri, Federica; Gentile, Maria Teresa; Passarella, Daniela; Caorsi, Calentina; Diaspro, Alberto; Taglialatela, Maurizio; Pagano, Aldo; Colucci-D'Amato, Luca; Florio, Tullio; Russo, Claudio.

In: Journal of Alzheimer's Disease, Vol. 29, No. 1, 2012, p. 211-227.

Research output: Contribution to journalArticle

Nizzari, M, Barbieri, F, Gentile, MT, Passarella, D, Caorsi, C, Diaspro, A, Taglialatela, M, Pagano, A, Colucci-D'Amato, L, Florio, T & Russo, C 2012, 'Amyloid-β protein precursor regulates phosphorylation and cellular compartmentalization of microtubule associated protein tau', Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 211-227. https://doi.org/10.3233/JAD-2011-101590
Nizzari, Mario ; Barbieri, Federica ; Gentile, Maria Teresa ; Passarella, Daniela ; Caorsi, Calentina ; Diaspro, Alberto ; Taglialatela, Maurizio ; Pagano, Aldo ; Colucci-D'Amato, Luca ; Florio, Tullio ; Russo, Claudio. / Amyloid-β protein precursor regulates phosphorylation and cellular compartmentalization of microtubule associated protein tau. In: Journal of Alzheimer's Disease. 2012 ; Vol. 29, No. 1. pp. 211-227.
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