Amyloid-β 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 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.
Dipartimento di Oncologia, Biologia e Genetica, Università degli Studi di Genova, Genova, Italy.
Mario
M
Nizzari
Federica
F
Barbieri
Maria Teresa
MT
Gentile
Daniela
D
Passarella
Calentina
C
Caorsi
Alberto
A
Diaspro
Maurizio
M
Taglialatela
Aldo
A
Pagano
Luca
L
Colucci-D'Amato
Tullio
T
Florio
Claudio
C
Russo
D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010766:Phosphorylation; D013347:Subcellular Fractions / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; D016875:tau Proteins