Physics of Protein Aggregation in Normal and Accelerated Brain Aging

Authors

Alberto J. Espay, James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.
Andrea Sturchio, Section of Neurology, Karolinska Institutet, Stockholm, Sweden.
Alberto Imarisio, Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Emily J. Hill, James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.
Brady Williamson, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Kora Montemagno, Center for functionally integrative neuroscience, Institute for Clinical Medicine, Aarhus University, Aarhus, Denmark.
Christian Hoffmann, Laboratory of Molecular Neuroscience, German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
Hugo Le Roy, Institute of Physics, School of Basic Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Dragomir Milovanovic, Laboratory of Molecular Neuroscience, German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
Fredric P. Manfredsson, Department of Translational Neuroscience and the Muhammad Ali Parkinson Center, Barrow Neurological Institute, Phoenix, Arizona, USA.

Document Type

Article

Abstract

Protein aggregation is a normal response to age-related exposures. According to the thermodynamic hypothesis of protein folding, soluble proteins precipitate into amyloids (pathology) under supersaturated conditions through a process similar to crystallization. This soluble-to-insoluble phase transition occurs via nucleation and may be catalyzed by ectopic surfaces such as lipid nanoparticles, microbes, or chemical pollutants. The increasing prevalence of these exposures with age correlates with the rising incidence of pathology over the lifespan. However, the formation of amyloid fibrils does not inherently cause neurodegeneration. Neurodegeneration emerges when the levels of functional monomeric proteins, from which amyloids form, fall below a critical threshold. The preservation of monomeric proteins may explain neurological resilience, regardless of the extent of amyloid deposition. This biophysical framework challenges the traditional clinicopathological view that considers amyloids intrinsically toxic, despite the absence of a known mechanism of toxicity. Instead, it suggests that chronic exposures driving persistent nucleation consume monomeric proteins as they aggregate. In normal aging, replacement matches loss; in accelerated aging, it does not. A biophysical approach to neurodegenerative diseases has important therapeutic implications, refocusing treatment strategies from removing pathology to restoring monomeric protein homeostasis above the threshold needed to sustain normal brain function.

Keywords

Alzheimer's disease, Parkinson's disease, amyloid, cross‐beta, nucleation, seed amplification assay, supersaturation

Medical Subject Headings

Humans; Aging (metabolism, pathology); Brain (metabolism, pathology); Amyloid (metabolism, chemistry); Protein Aggregates; Neurodegenerative Diseases (metabolism, pathology); Animals; Protein Aggregation, Pathological (metabolism); Protein Folding; Thermodynamics

Publication Date

8-1-2025

Publication Title

BioEssays : news and reviews in molecular, cellular and developmental biology

E-ISSN

1521-1878

Volume

47

Issue

8

First Page

e70030

PubMed ID

40539231

Digital Object Identifier (DOI)

10.1002/bies.70030

Recommended Citation

Espay, Alberto J.; Sturchio, Andrea; Imarisio, Alberto; Hill, Emily J.; Williamson, Brady; Montemagno, Kora; Hoffmann, Christian; Roy, Hugo Le; Milovanovic, Dragomir; and Manfredsson, Fredric P., "Physics of Protein Aggregation in Normal and Accelerated Brain Aging" (2025). Translational Neuroscience. 2474.
https://scholar.barrowneuro.org/neurobiology/2474