The Prion-Like Aspect of Alzheimer Pathology

Abstract

Many neurodegenerative disorders are characterized by a predictable spatiotemporal progression of the aggregation of specific proteins in the brain. The most prevalent cerebral proteopathy is Alzheimer’s disease (AD), in which aggregated amyloid-β peptide (Aβ) is deposited in the form of extracellular parenchymal plaques and vascular amyloid. Multiple lines of evidence indicate that β-amyloidosis can be exogenously induced by the application of brain extracts containing aggregated Aβ. The β-amyloid-inducing agent in the extract is likely Aβ itself in a conformation that cannot easily be mimicked with synthetic material. The induced Aβ lesions spread over time within and among brain regions, and they are dependent on the structural and biochemical nature of Aβ in the extract and on the characteristics of the host. We have found that bioactive Aβ seeds exist in both soluble and insoluble forms; some of them are sensitive to proteinase-K digestion and some are not. Observations of similar prion-like induction, spreading, and transmission of tau lesions, the second hallmark of AD pathology, and more recent observations of seeded α-synuclein lesions suggest that the concept of prion-like corruptive templating of proteins may also apply to intracellular lesions in neurodegenerative diseases. The clinical implications of these observations are not yet clear. The finding that the Aβ seeds are partly soluble suggests that such seeds in bodily fluids may have diagnostic value and also that they could represent a novel target for early therapeutic intervention. Furthermore, the possibility that mechanisms exist allowing for the transport of Aβ aggregates (and possibly other seeds) from the periphery to the brain raises the speculation that environmental amyloidogenic seeds might act as risk factors for certain neurodegenerative diseases.