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@ARTICLE{Espay:280046,
      author       = {Espay, Alberto J and Sturchio, Andrea and Imarisio, Alberto
                      and Hill, Emily J and Williamson, Brady and Montemagno, Kora
                      and Hoffmann, Christian and Roy, Hugo Le and Milovanovic,
                      Dragomir and Manfredsson, Fredric P},
      title        = {{P}hysics of {P}rotein {A}ggregation in {N}ormal and
                      {A}ccelerated {B}rain {A}ging.},
      journal      = {Bioessays},
      volume       = {47},
      number       = {8},
      issn         = {0265-9247},
      address      = {New York, NY},
      publisher    = {Wiley-Liss},
      reportid     = {DZNE-2025-00885},
      pages        = {e70030},
      year         = {2025},
      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.},
      subtyp        = {Review Article},
      keywords     = {Humans / Aging: metabolism / Aging: pathology / Brain:
                      metabolism / Brain: pathology / Amyloid: metabolism /
                      Amyloid: chemistry / Protein Aggregates / Neurodegenerative
                      Diseases: metabolism / Neurodegenerative Diseases: pathology
                      / Animals / Protein Aggregation, Pathological: metabolism /
                      Protein Folding / Thermodynamics / Alzheimer's disease
                      (Other) / Parkinson's disease (Other) / amyloid (Other) /
                      cross‐beta (Other) / nucleation (Other) / seed
                      amplification assay (Other) / supersaturation (Other) /
                      Amyloid (NLM Chemicals) / Protein Aggregates (NLM
                      Chemicals)},
      cin          = {AG Milovanovic (Berlin)},
      ddc          = {540},
      cid          = {I:(DE-2719)1813002},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40539231},
      pmc          = {pmc:PMC12278810},
      doi          = {10.1002/bies.70030},
      url          = {https://pub.dzne.de/record/280046},
}