Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders

Abstract

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.

Figure 1. The accumulation of misfolded proteins in AD follows characteristic and predictable patterns

Cross-sectional autopsy studies indicate that β-amyloid plaques (A) first appear in the neocortex, followed by the allocortex and finally subcortical regions. In the brain, neurofibrillary tangles (B) occur first in the locus coeruleus and transentorhinal area and then spread to the amygdala and interconnected neocortical brain regions^, . The relatively stereotyped patterns of expansion suggest the involvement of neuronal transport mechanisms in the spread of proteopathic seeds. Increasing density of shading indicates increasing pathology. The schemata with the progression of the Aβ and tau lesions have been modified from previous publications.

Figure 2. Induction and spread of Aβ lesions in a transgenic mouse model

(A) Stainless-steel wire segments were coated with Aβ-rich brain extract, dried, and implanted unilaterally into the hippocampus of APP23 transgenic mice. Four months later, immunohistochemical analysis with an anti-Aβ-antibody revealed strong local induction of Aβ-deposits in the vicinity of the wire (arrowhead in the middle section of three coronal sections along the anterior-posterior (AP) axis through the hippocampus). Higher magnification of the dentate gyrus double-stained with anti-Aβ-antibody and Congo red revealed spreading of Aβ-deposition thoughout the dentate gyrus (distance between the sections shown: 600μm). Reproduced from with permission. (B) The injection of Aβ-rich brain extracts induces Aβ aggregation within the injected brain region, as shown here for the entorhinal cortex (EC) in APP23 transgenic mice (asterisk). However EC injections also induce β-amyloid deposition (arrows) in the outer molecular layer (OML) of the hippocampal dentate gyrus (DG), a region that is non-contiguous but is axonally interconnected with the injection site. For details of the methods, see.