Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade

Issue title: Alzheimer’s Disease: New Beginnings

Guest editors: G. Perry, J. Avila, P.I. Moreira, A.A. Sorensen and M. Tabaton

Article type: Review Article

Authors: Gulisano, Walter^a | Maugeri, Daniele^a | Baltrons, Marian A.^{c; d} | Fà, Mauro^c | Amato, Arianna^e | Palmeri, Agostino^a | D’Adamio, Luciano^f | Grassi, Claudio^g | Devanand, D.P.^{c; h} | Honig, Lawrence S.^{c; i} | Puzzo, Daniela^{a; *} | Arancio, Ottavio^{b; c; *}

Affiliations: [a] Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy | [b] Department of Pathology and Cell Biology, Columbia University, New York, NY, USA | [c] Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA | [d] Department of Biochemistry and Molecular Biology and Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain | [e] Department of Anaesthesiology, Università Cattolica del Sacro Cuore, Rome, Italy | [f] Department of Pharmacology, Physiology and Neuroscience, Rutgers University, Newark, NJ, USA | [g] Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy | [h] Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA | [i] Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY, USA

Correspondence: [*] Correspondence to: Ottavio Arancio, Department of Pathology and Cell Biology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Department of Medicine, P&S #12-420D 630W 168th St., New York, NY 10032, USA. Tel.: +1 212 342 0533; Fax: +1 212 342 9096; E-mail: [email protected] and Daniela Puzzo, Department of Biomedical and Biotechnological Sciences, Section of Physiology, Via Santa sofia 89 – Torri Biologiche, Catania, 95123, Italy. Tel.: +39 095 4781322; E-mail: [email protected].

Abstract: The “Amyloid Cascade Hypothesis” has dominated the Alzheimer’s disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.

Keywords: Amyloid-β peptide, amyloid-β protein precursor, oligomers, synaptic dysfunction, tau

DOI: 10.3233/JAD-179935

Journal: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S611-S631, 2018