Propagation Mechanisms of Amyloid Pathology in Neurodegenerative Diseases

Amyloid pathology underpins a range of neurodegenerative disorders, most notably Alzheimer’s disease, where aggregation of amyloid-β (Aβ) peptides drives a cascade of molecular events leading to synaptic dysfunction, neuroinflammation and neuronal loss. Misfolded proteins act as seeds, templating the conversion of normally folded counterparts into pathological assemblies. These seeds spread through brain networks via synaptic connections, extracellular diffusion and uptake by neighbouring cells. Distinct structural variants or strains of Aβ exhibit different kinetics of aggregation and resistance to clearance, accounting for clinical heterogeneity. Vascular deposition of Aβ in the form of cerebral amyloid angiopathy further amplifies tissue injury and may facilitate bidirectional exchange between the central nervous system and peripheral compartments. An emerging body of work reveals that peripheral organs can clear or harbour Aβ seeds, influencing central burden. Understanding the balance between seeding, spread and clearance is essential for devising interventions that arrest propagation at multiple levels, from molecular inhibitors of aggregation to immunotherapies that target circulating seeds.

Research from Nature Portfolio

Recent studies have shown that iatrogenic exposure to pathogenic Aβ seeds can induce Alzheimer-like pathology decades later. Analysis of individuals treated with cadaveric pituitary-derived growth hormone revealed the long-term development of amyloid plaques and vascular Aβ deposits in the absence of genetic predisposition, demonstrating that Aβ assemblies can act as transmissible seeds under clinical conditions. Complementary work on molecular subtypes of Alzheimer’s disease has identified distinct Aβ conformational strains with unique biochemical signatures. When inoculated into animal models, each strain propagated its specific aggregation pattern and distribution, yielding divergent neuropathological phenotypes. These findings underscore the concept that Aβ propagation is strain-dependent and that targeting particular conformers may be crucial for personalised therapeutic strategies.

Propagation Mechanisms of Amyloid Pathology in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in propagation mechanisms of amyloid pathology in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Amyloid-β (Aβ): Peptide fragments of amyloid precursor protein that can misfold and aggregate in brain tissue.

Prion-like seeding: Mechanism by which misfolded proteins template the conversion of native proteins into pathological conformers.

Cerebral amyloid angiopathy (CAA): Deposition of Aβ in the walls of cerebral blood vessels, leading to vascular dysfunction and haemorrhage.

Conformational strain: Structurally distinct form of aggregated protein that dictates its propagation kinetics and toxicity.

Seed amplification assay (SAA): In vitro technique that amplifies trace amounts of misfolded protein seeds to detectable levels.

Surface-enhanced Raman spectroscopy (SERS): Analytical method that enhances Raman scattering signals for molecular fingerprinting of protein aggregates.

References

1. Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone. Nature Medicine (2024).
2. Alzheimer’s disease: targeting the peripheral circulation. Molecular Neurodegeneration (2023).
3. Impact of seed amplification assay and surface-enhanced Raman spectroscopy combined approach on the clinical diagnosis of Alzheimer’s disease. Translational Neurodegeneration (2023).
4. Peripheral clearance of brain-derived Aβ in Alzheimer's disease: pathophysiology and therapeutic perspectives. Translational Neurodegeneration (2020).
5. Dura mater is a potential source of Aβ seeds. Acta Neuropathologica (2016).
6. Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura. Annals of Neurology (2019).
7. Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery. Acta Neuropathologica (2018).
8. Molecular subtypes of Alzheimer’s disease. Scientific Reports (2018).