Open AccessNeurodegeneration in an Aβ‐induced model of Alzheimer’s disease: the role of Cdk5
Author(s) -
Lopes Joao P.,
Oliveira Catarina R.,
Agostinho Paula
Publication year - 2010
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2009.00536.x
Subject(s) - cyclin dependent kinase 5 , calpain , neurodegeneration , hyperphosphorylation , biology , microbiology and biotechnology , kinase , programmed cell death , neuroscience , apoptosis , huntington's disease , protein kinase a , medicine , biochemistry , disease , cyclin dependent kinase 2 , enzyme
Summary Cdk5 dysregulation is a major event in the neurodegenerative process of Alzheimer’s disease (AD). In vitro studies using differentiated neurons exposed to Aβ exhibit Cdk5‐mediated tau hyperphosphorylation, cell cycle re‐entry and neuronal loss. In this study we aimed to determine the role of Cdk5 in neuronal injury occurring in an AD mouse model obtained through the intracerebroventricular (icv) injection of the Aβ 1–40 synthetic peptide. In mice icv‐injected with Aβ, Cdk5 activator p35 is cleaved by calpains, leading to p25 formation and Cdk5 overactivation. Subsequently, there was an increase in tau hyperphosphorylation, as well as decreased levels of synaptic markers. Cell cycle reactivation and a significant neuronal loss were also observed. These neurotoxic events in Aβ‐injected mice were prevented by blocking calpain activation with MDL28170 , which was administered intraperitoneally (ip). As MDL prevents p35 cleavage and subsequent Cdk5 overactivation, it is likely that this kinase is involved in tau hyperphosphorylation, cell cycle re‐entry, synaptic loss and neuronal death triggered by Aβ. Altogether, these data demonstrate that Cdk5 plays a pivotal role in tau phosphorylation, cell cycle induction, synaptotoxicity, and apoptotic death in postmitotic neurons exposed to Aβ peptides in vivo , acting as a link between diverse neurotoxic pathways of AD.