TY  - JOUR
AU  - Espay, Alberto J
AU  - Sturchio, Andrea
AU  - Imarisio, Alberto
AU  - Hill, Emily J
AU  - Williamson, Brady
AU  - Montemagno, Kora
AU  - Hoffmann, Christian
AU  - Roy, Hugo Le
AU  - Milovanovic, Dragomir
AU  - Manfredsson, Fredric P
TI  - Physics of Protein Aggregation in Normal and Accelerated Brain Aging.
JO  - Bioessays
VL  - 47
IS  - 8
SN  - 0265-9247
CY  - New York, NY
PB  - Wiley-Liss
M1  - DZNE-2025-00885
SP  - e70030
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Aging: metabolism
KW  - Aging: pathology
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Amyloid: metabolism
KW  - Amyloid: chemistry
KW  - Protein Aggregates
KW  - Neurodegenerative Diseases: metabolism
KW  - Neurodegenerative Diseases: pathology
KW  - Animals
KW  - Protein Aggregation, Pathological: metabolism
KW  - Protein Folding
KW  - Thermodynamics
KW  - Alzheimer's disease (Other)
KW  - Parkinson's disease (Other)
KW  - amyloid (Other)
KW  - cross‐beta (Other)
KW  - nucleation (Other)
KW  - seed amplification assay (Other)
KW  - supersaturation (Other)
KW  - Amyloid (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40539231
C2  - pmc:PMC12278810
DO  - DOI:10.1002/bies.70030
UR  - https://pub.dzne.de/record/280046
ER  -