nELAV Proteins Alteration in Alzheimer's Disease Brain: A Novel Putative Target for Amyloid-β Reverberating on AβPP Processing

Article type: Research Article

Authors: Amadio, Marialaura^{a; b; f; 1; *} | Pascale, Alessia^{a; 1} | Wang, Jun^{b; c; f} | Ho, Lap^{b; c; f} | Quattrone, Alessandro^{g; h} | Gandy, Sam^{d; f} | Haroutunian, Vahram^{b; c; f} | Racchi, Marco^a | Pasinetti, Giulio Maria^{b; c; e; f}

Affiliations: [a] Department of Experimental and Applied Pharmacology and Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy | [b] Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA | [c] Department of Neuroscience, The Mount Sinai School of Medicine, New York, NY, USA | [d] Department of Neurology, The Mount Sinai School of Medicine, New York, NY, USA | [e] Department of Geriatric and Adult Development, The Mount Sinai School of Medicine, New York, NY, USA | [f] The James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA | [g] Centre for Integrative Biology, University of Trento, Mattarello (TN), Italy | [h] Engineering and Information Science Department, University of Trento, Mattarello (TN), Italy

Correspondence: [*] Corresponding author: Marialaura Amadio, Department of Experimental and Applied Pharmacology, University of Pavia, Via Taramelli 14, 27100 Pavia, Italy, Tel.: +39 0382 987961; Fax: +39 0382 987405; E-mail: [email protected].

Note: [1] These authors contributed equally to the paper.

Abstract: Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). Indeed, we found that the content of nELAV proteins is significantly decreased along with clinical dementia progression in the hippocampi of AD brains, where it inversely correlates with the amount of amyloid-β (Aβ). To check the direct influence of Aβ on nELAV, we performed in vitro experiments using human SH-SY5Y cells, finding that Aβ1–42 specifically determines nELAV proteins reduction. Since ADAM10 mRNA has the predicted sequences targeted by nELAV, we investigated whether Aβ, through nELAV proteins, could originate a vicious circle affecting amyloid-β protein precursor (AβPP) processing. Immunoprecipitation experiments showed that indeed nELAV proteins bind to ADAM10 mRNA and that this binding is disrupted by Aβ1–42 exposure, resulting in a decreased ADAM10 protein expression. ADAM10 protein diminution was also found in AD hippocampi. These data show for the first time the involvement of nELAV in AD pathology and suggest that their alteration may affect genes implicated in AβPP processing.

Keywords: ADAM10, Alzheimer's disease, amyloid-β, amyloid-β protein precursor processing, nELAV

DOI: 10.3233/JAD-2009-0967

Journal: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 409-419, 2009