Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease

ABSTRACT

Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP^Sc). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ∼30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.

KEYWORDS:

• Amyloid beta
• Alzheimer's disease
• human prion strains
• neurodegeneration

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Acknowledgments

The authors are grateful to the patient's families, the CJD Foundation, and all the members of the National Prion Disease Pathology Surveillance Center.

Funding

This work was supported by grants from NIH (NS074317), CDC (UR8/CCU515004), Spitz Fund, and the Charles S. Britton Fund.