Oncotarget

Research Papers:

The c-jun N-terminal kinase plays a key role in ocular degenerative changes in a mouse model of Alzheimer disease suggesting a correlation between ocular and brain pathologies

Lucia Buccarello, Alessandra Sclip, Matteo Sacchi, Anna Maria Castaldo, Ilaria Bertani, Andrea ReCecconi, Silvia Maestroni, Gianpaolo Zerbini, Paolo Nucci and Tiziana Borsello _

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Oncotarget. 2017; 8:83038-83051. https://doi.org/10.18632/oncotarget.19886

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Abstract

Lucia Buccarello1, Alessandra Sclip1, Matteo Sacchi3, Anna Maria Castaldo1, Ilaria Bertani1, Andrea ReCecconi1, Silvia Maestroni4, Gianpaolo Zerbini4, Paolo Nucci3 and Tiziana Borsello1,2

1IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy

2Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

3University Eye Clinic, San Giuseppe Hospital, University of Milan, Milan, Italy

4Unità Complicanze del Diabete, Istituto Scientifico San Raffaele, Milan, Italy

Correspondence to:

Tiziana Borsello, email: [email protected], [email protected]

Keywords: Alzheimer’s disease, stress signaling pathway, JNK, retinal ganglion cell layer, optical coherence tomography

Received: May 04, 2017    Accepted: July 12, 2017    Published: August 03, 2017

ABSTRACT

Recently a range of ocular manifestations such as retinal and lens amyloid-beta accumulation and retinal nerve fiber layer loss have been proposed as potential biomarkers in Alzheimer disease (AD). The TgCRND8 mouse model of AD exhibits age-dependent amyloid β (Aβ) oligomers accumulation and cognitive defects, amyloid plaques and hyperphosphorylated Tau deposition and inflammation. We proved the correlation between ocular pathologies and AD, observing increased levels of p-APP and p-Tau, accumulation of Aβ oligomers in the retina, eye, and optic nerve. The accumulation of amyloid markers was significantly stronger in the retinal ganglion cell (RGC) layer, suggesting that RGC might be more susceptible to degeneration. We detected a thinning of the RGC layer as well as RGC death in the retina of TgCRND8 mice, by using a combination of Optical Coherence Tomography (OCT), immunofluorescence, immunohistochemistry and Western blotting techniques. We proved for the first time the key role of C-Jun N-terminal Kinase (JNK) in the ocular degeneration. In support of this, the administration of the JNK inhibitor, D-JNKI1, was able to counteract the Aβ and p-Tau accumulation in the retina of TgCRND8 mice, and consequently reduce RGCs loss. These results confirm that degenerative changes in the retina/eye of AD mouse model mirrors the events observed in the brain parenchyma. Ocular changes can be detected by non-invasive imaging techniques, such as OCT, to study and test different therapeutic strategies against degenerative events associated to AD.


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