Affiliations: [a] James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA
| [b] Department of Clinical Neuroscience, Neuro Svenningsson, Karolinska Institute, 171 76 Stockholm, Sweden
| [c] Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| [d] Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden
Correspondence:
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Correspondence to: Alberto J. Espay, MD, MSc, FAAN, Professor of Neurology, University of Cincinnati Academic Health Center, 260 Stetson St., Suite 2300, Cincinnati, OH 45267-0525, USA. Tel.: +1 513 558 4035; Fax: +1 513 558 7015; E-mails: alberto.espay@uc.edu, aespay@gmail.com.
Abstract: Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-β conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer’s disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-β levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-β, however, would only exemplify ‘rescue medicine.’ Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer’s disease and other neurodegenerative disorders.
