Journal
ONCOTARGET
Volume 8, Issue 47, Pages 83038-83051Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.19886
Keywords
Alzheimer's disease; stress signaling pathway; JNK; retinal ganglion cell layer; optical coherence tomography
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Funding
- ADDF (Alzheimer's Drugs Discovery Foundation) USA
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Recently a range of ocular manifestations such as retinal and lens amyloidbeta 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 beta(A beta) 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 A beta 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 A beta 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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