Physics of Protein Aggregation in Normal and Accelerated Brain Aging

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.

FIGURE 1

A reactive brain in health and disease. An external nucleation surface (such as that provided by herpes simplex virus type 1, in this example) catalyzes the reactive precipitation (polymerization) of normal monomers of Aβ42 into amyloid. Treatment against the pathogen (an antiviral in this example) eliminates the catalyst, preventing further polymerization of Aβ42, and maintaining high levels of the peptide. Delayed or lack of treatment perpetuates the polymerization and depletes the pool of polypeptides, potentially depriving neurons of crucial protein function and causing degeneration. Figure was created using Biorender tools.

FIGURE 2

Active vs. passive growth. The growth of living organisms is an active process that depends on replication (nucleic acid required); the growth of non‐living matter can be passive, and does not require machinery for replication—as, for example, the spread of ice on a window during the winter. The phase transition of water into ice is an example of passive “growth” via crystallization. The growth or “spread” of pathology in neurodegenerative disorders reflects the transition of normal proteins without net gain (pathology is the relative insoluble fraction of former soluble monomeric precursors), unlike the net gain of cancers. Figure was created using Biorender tools.

FIGURE 3

Amyloid structure. (A) Side‐view of a protofilament comprising multiple layers of monomers of the 42‐amino acid residue of amyloid‐β (Aβ42) separated by 4.8 Å. The amino acids (stripe colors) are stacked on top of each other in the common parallel in‐register arrangement. (B) Top‐view of the same protofilament. Arrows denote different cross‐β steric zippers between different stretched sequences of the peptide with interacting sidechains. Images created using Mol* [159] from PDB structure 2MXU from a paper by Xiao et al. 2015 [160].

FIGURE 4

Supersaturation and nucleation. Below the solubility threshold, α‐synuclein monomers are natively folded in their thermodynamically stable state. In the intermediate energetic state (metastable), there is no spontaneous nucleation without a catalyzed lowering of the nucleation barrier by adding seeds (preformed nuclei) or heterogenous surfaces (viruses, lipid membranes, nanoparticles). Seeds catalyze the nucleation phase without a lag time (the experimental condition in the αSyn‐seed amplification assay [αSyn‐SAA]). With more significant supersaturation, the nucleation barrier is overcome, and nucleation proceeds spontaneously after a lag time. SAA figures in the right panel were created using Biorender tools.

FIGURE 5

Native vs. amyloid protein folding and heterogeneous nucleation. (A) Amyloids grow like dendritic crystals, mediated by primary or secondary nucleation on the surface of a preformed nucleus (seed). There is no energy source or mechanism by which the seed can restrict growth to the tips, as proposed by the prion hypothesis. (B) Proteins assume their thermodynamically favorable (lower energy) native conformation based on specific interactions between the sidechains of their primary sequence under sub‐saturated conditions. Under super‐saturated conditions, greater molecular proximity makes unspecific intermolecular interactions more favorable. Partially folded proteins occupy a higher energy state than fully folded proteins and have a reduced nucleation barrier for aggregation. Preformed nuclei (seeding) or heterogeneous surfaces (heterogeneous nucleation) lowers the nucleation barrier, catalyzing the phase transition into amyloids. Heterogeneous surfaces may have exogenous (e.g., virus particles) or endogenous origins (e.g., disrupted sphingolipid membrane composition in GBA gene variants). Modified with permission from Ezzat et al. [73]. Figure was created using Biorender tools.