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Title: C-Jun-N-terminal kinase regulates Aβ oligomers production, synapthopathy and cognitive deficits in Alzheimer's disease
Author: Sclip, Alessandra
ISNI:       0000 0004 5348 2955
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2014
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Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by Amyloid-B CAP) and tau deposition in the brain. The number of patients suffering AD is estimated at 36 million worldwide, making AD the most common fonn of dementia. There is no efficient therapy for AD, thus efforts to develop new pharmacological strategies to treat AD need to be intensified. Increasing evidence establishes a central role of soluble and oligomeric form of AP peptide in the pathogenesis of AD. AP accumulates in the synaptic compartment and disrupts the synaptic functionality, leading at least to synaptic loss and neurodegeneration. These events strongly correlate with cognitive deficits characteristic of the pathology. The mechanisms promoting AP production as well as the intracellular pathways responsible for synaptic degeneration are not well known. Objective of this study was thus to decipher the signaling pathways involved in A~ oligorners toxicity, focusing on cj Jun N-terminal kinase (JNK). JNK has been extensively studied for its role in stress stimuli and AD. Here we found that JNK participates to the production of AP oiigomers, promoting phosphorylation of APP at Thr668 residue. Moreover we reported a strong activation of the JNK pathway in the synaptic compartment in both in vitro and in vivo models of synaptopathy. This correlates with the reduction of dendritic spines density and a decrease of postsynaptic markers (AMP AR and NMDAR subunits, PSD-95 and drebrin). To confirm the involvement of JNK in synaptic degeneration induced by AP oligomers we phannacologically inhibited JNK action, using the specific cell permeable peptide, D-JNKll. Treatment with D-JNKII reduces the amyloidogenic cleavage of APP, and thus the production of AP oiigomers. Moreover, D-JNKll reverts synaptic degeneration preventing loss of dendritic spines and proteins from the postsynaptic membrane. Finally, the peptide prevents long term potentiation and long term depression alterations and completely reverts cognitive deficits. These results provide essential new infotmation about the molecular changes that ultimately lead to the disruption of synaptic functionality and validate JNK inhibition as a new pharmacological strategy for the treatment of AD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available