Affiliations: [a] Department of Experimental Medicine and Oncology, General Pathology Section, University of Torino, Torino, Italy | [b] Neuroscience Institute of the Cavalieri Ottolenghi Foundation (NICO), University of Torino, Torino, Italy | [c] The Litwin-Zucker Research Center for the Study of Alzheimer's Disease-The Feinstein Institute for Medical Research, North Shore – LIJ, Manhasset, NY, USA | [d] Department of Neurosciences, Ophtalmology and Genetics, University of Genova, Genova, Italy | [e] Department of Internal Medicine, University of Genova, Genova, Italy
Correspondence:
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Correspondence to: Elena Tamagno, Neuroscience Institute of the Cavalieri Ottolenghi Foundation Regione Gonzole 10, 10046 Orbassano (Torino), Italy. Tel.: +39 011 6707758/6604; Fax: +39 011 2367753; E-mail: elena.tamagno@unito.it; and Massimo Tabaton, Unit of Geriatric Medicine, Department of Internal Medicine, University of Genova, 16132 Genova, Italy. Tel.: +39 010 3537064; Fax: +39 010 506938; E-mail: mtabaton@neurologia.unige.it.
Abstract: The sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the amyloid-β protein precursor (AβPP) result in the production of the amyloid-β (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of small, soluble aggregates of Aβ42 is the major pathogenic event of Alzheimer's disease (AD). However, the physiologic activity of Aβ peptides is still elusive. Here, we show that expression of BACE1 is regulated by Aβ42, which augments BACE1 gene transcription through the JNK/c-jun signaling pathway. Of note, Aβ40 has much less effect on BACE1 expression. These findings unveil a positive feedback loop in which γ-secretase cleavage of AβPP releases a functionally-active peptide, Aβ42, that promotes BACE1 transcription. Thus, gene expression induced by Aβ42 may have implications in the neuronal dysfunction and degeneration that occurs in AD.
