Affiliations: [a] Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland
| [b] Division of Nuclear Medicine and Molecular Imaging, Diagnostic Department, Geneva University Hospitals, and NimtLab, Faculty of Medicine, Geneva University, Geneva, Switzerland
| [c] Division of Radiation Oncology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, Geneva University, Geneva, Switzerland
| [d] IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Correspondence:
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Correspondence to: Thomas Zilli, MD, Radiation Oncology Division, Geneva University Hospitals, 1211, Geneva 14, Switzerland. Tel.: +41 0 22 372 70 90; E-mail: thomas.zilli@hcuge.ch.
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by extracellular amyloid-β (Aβ) peptide aggregates, forming amyloid plaques, and intracellular deposits of phosphorylated tau. Neuroinflammation is now considered as the third hallmark of AD. The majority of clinical trials tested pharmacological strategies targeting amyloid, tau, and neuroinflammation, with disappointing results overall. In parallel, innovative strategies exploring other pathways and approaches are being tested. In this article, we focus on the rationale and preliminary preclinical evidence for a novel application to AD of a widely used therapeutic strategy for oncological and benign conditions: low-dose radiation therapy (LD-RT). LD-RT has shown to be effective against systemic amyloid deposits, as well as against chronic inflammatory diseases, and could thus be able to modulate amyloid load and neuroinflammation in AD. The anti-amyloid effect could be possibly mediated by the LD-RT action on the β-sheet structure of amyloid fibrils, by breaking H-bonds, and depolymerize glucoaminoglycans which are highly radiation-sensitive molecules associated with amyloid fibrils. The anti-inflammatory effect could be linked to the decrease of leukocytes-endothelial cells interactions and to the stimulation of the release of anti-inflammatory molecules. One preclinical study has observed a dramatic reduction of amyloid plaques 4 weeks post-RT, more important with fractionated protocols at low doses than hypofractionated single dose treatments, associated with modulation of inflammatory and anti-inflammatory cytokines and cognitive improvement. Ongoing Phase I clinical trials will test the ability of LD-RT to hold these promises.
