Profiling Prion-Like Strains of Aβ that Control Alzheimer’s Progression

Jiri Safar, MD
Case Western Reserve University (Cleveland, OH)
Year Awarded:
Grant Duration:
July 1, 2016 to June 30, 2019
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Midwestern
Jiri Safar, MD

Profiling Structure and Biology of Beta Amyloid Strains


We believe our project addresses a confounding puzzle: Why clinical symptomatology, severity, and progression rates of late-onset Alzheimer disease (AD) frequently do not coincide with the total beta amyloid (Aβ) load? We propose to test the hypothesis that rapid progression of the disease is caused by specific molecular structural features of Aβ. The findings have the potential to significantly improve our understanding of AD and to establish progression rate-directed diagnostics and therapeutic interventions as a key strategy for delaying and preventing symptomatic AD.


The findings generated in this project have a potential to significantly improve our understanding of Alzheimer diseases (AD) and to establish transgenic mice models of Alzheimer’s disease (AD) replicating important characteristics of human disease. Such models are critical for the development of progression rate-directed diagnostics and therapeutics. We also anticipate that translating the methods developed for molecular characterization of brain Aβwill significantly improve the predictive value, specificity, and sensitivity of plasma and cerebrospinal fluid (CSF) tests for AD and provide the basis for individual risk assessment and therapeutic monitoring. Moreover, the new data generated in this proposal provide a foundation for long term advanced structural studies of brain Aβ and the mechanism(s) of accumulation in the brain. Finally, improved understanding of the molecular mechanism responsible for different progression rates of the disease should translate to the design of new structure-based therapeutic interventions with the potential to slow down AD progression as a key strategy for delaying and ultimately preventing symptomatic stages of the disease.

About the Researcher

Dr. Jiri G. Safar is director of the National Prion Disease Pathology Surveillance Center (NPDPSC) and associate professor in the Departments of Pathology and Neurology at Case Western Reserve University (CWRU). After completing his residency, chief residency, and PhD training in biochemistry, he completed research fellowship in the laboratory of Central Nervous System Studies at the National Institutes of Health (NIH), directed by D.C. Gajdusek (Nobel Prize for Medicine, 1976). In 1996, he took a position of a senior scientist at the Institute for Neurodegenerative Diseases, directed by Stanley B. Prusiner (Nobel Prize for Medicine, 1997) and associate professor at the University of California at San Francisco (UCSF). In 2008, Dr. Safar was recruited to continue his research on neurodegenerative diseases caused by prions and protein misfolding at CWRU. His extensive research has led to the discovery of previously unknown forms of prions and prion diseases; a better understanding of the conformation of prion proteins; the unraveling of the molecular mechanisms of prion strains; and the development of new methods for detection and differentiation of misfolded proteins and prions and other misfolded proteins. The focus of Dr. Safar's current research is on understanding the mechanism of replication of human prions and other misfolded proteins and elucidating molecular mechanisms of neurodegeneration in Alzheimer and prion diseases. Dr. Safar has authored 116 publications and holds 27 U.S. and international patents.

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Personal Story

While my training was predominantly in prion diseases, new evidence now argues that structurally distinct amyloid particles play a major role in the remarkably diverse features of Alzheimer disease (AD), Parkinsonism, and other neurodegenerative disorders, and may behave as distinct prion-like strains encoding diverse disease characteristics. From these observations and our growing understanding of prions, there is a critical need for new approaches to diagnostic and therapeutic strategies for protein aggregates causing these elusive disorders. The methods and principles developed for studies of prions are directly applicable to AD and other neurodegenerative diseases. Applying them is essential for development of effective treatments of AD, which will require drugs that enhance clearance of pathogenic protein aggregates, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.

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