Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders

By Mathias Jucker, Lary C. Walker. Annals of Neurology, 2011

610 citations recorded by the source corpus.

The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β‐amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism—corruptive protein templating. Experimentally, cerebral β‐amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid‐inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α‐synuclein, huntingtin, superoxide dismutase‐1, and TDP‐43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism‐based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders. Ann Neurol 2011;70:532–540

Subfields: Molecular Biology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/a083431598aa8300a06d560a5e6377c2d187348a

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Citations in the corpus

Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury (2014, background): “Emerging evidence suggests that the movement of tau and tau aggregates through the extracellular space plays an important role in the development and spread of intracellular tau pathology (Frost and Diamond, 2010; Jucker and Walker, 2011; Walker et al., 2013).”
The Glymphatic System – A Beginner's Guide (2015, neutral): “initiation of fibrillary aggregates, which attracts additional tau leading to formation of neurofibrillary tangles ultimately resulting in a prion-like spread of the pathology [101, 102].”
Predicting regional neurodegeneration from the healthy brain functional connectome. (2012, background): “Providing a more parsimonious account, growing evidence suggests that prion-like mechanisms may promote the spread of toxic, misfolded, nonprion protein species between interconnected neurons (Baker et al., 1993, 1994; Brundin et al., 2010; Clavaguera et al., 2009; Frost and Diamond, 2010; Frost et ”