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Role of Cyclin-Dependent Kinase 5 in the Neurodegenerative Process Triggered by Amyloid-Beta and Prion Peptides: Implications for Alzheimer’s Disease and Prion-Related Encephalopathies

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Abstract

Tau hyperphosphorylation, amyloid plaques, and neuronal death are major neuropathological features of Alzheimer’s disease (AD) and Prion-related encephalopathies (PRE). Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase, active in post-mitotic neurons, where it regulates survival and death pathways. Overactivation of Cdk5 is conferred by p25, a truncated fragment of the p35 activator formed upon calpain activation. Cdk5 deregulation causes abnormal phosphorylation of microtubule-associated protein tau, leading to neurodegeneration. In this work we investigated the involvement of Cdk5 in the neurodegeneration triggered by amyloid-beta (Aβ) and prion (PrP) peptides, the culprit agents of AD and PRE. As a work model, we used cultured rat cortical neurons treated with Aβ1–40 and PrP106–126 synthetic peptides. The obtained data show that apoptotic neuronal death caused by both the peptides was in part due to Cdk5 deregulation. After peptide treatment, p25 levels were significantly enhanced in a pattern consistent with the augment in calpain activity. Moreover, Aβ1–40 and PrP106–126 increased the levels of tau protein phosphorylated at Ser202/Thr205. Cdk5 (roscovitine) and calpain (MDL28170) inhibitors reverted tau hyperphosphorylation and prevented neuronal death caused by Aβ1–40 and PrP106–126. This study demonstrates, for the first time, that Cdk5 is involved in PrP-neurotoxicity. Altogether, our data suggests that Cdk5 plays an active role in the pathogenesis of AD and PRE.

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Authors and Affiliations

  1. Faculty of Medicine, Center for Neuroscience and Cell Biology, Biochemistry Institute, University of Coimbra, 3004, Coimbra, Portugal

    Joao P. Lopes, Catarina R. Oliveira & Paula Agostinho

  2. Department of Zoology, Center for Neuroscience and Cell Biology, University of Coimbra, 3004, Coimbra, Portugal

    Paula Agostinho

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  1. Joao P. Lopes
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  2. Catarina R. Oliveira
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  3. Paula Agostinho
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Correspondence to Paula Agostinho.

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Lopes, J.P., Oliveira, C.R. & Agostinho, P. Role of Cyclin-Dependent Kinase 5 in the Neurodegenerative Process Triggered by Amyloid-Beta and Prion Peptides: Implications for Alzheimer’s Disease and Prion-Related Encephalopathies. Cell Mol Neurobiol 27, 943–957 (2007). https://doi.org/10.1007/s10571-007-9224-3

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