News Release
 

June 27, 2011

CONTACT: Karen Kreeger
215-349-5658
karen.kreeger@uphs.upenn.edu

Penn Medicine - University of Pennsylvania School of Medicine and University of Pennsylvania Health System


This release is available online at
http://www.uphs.upenn.edu/news/News_Releases/2011/06/mistaken-identity/

Case of Mistaken Identity: Penn Study Questions Role of A-beta Molecules in Alzheimer's Disease Pathology

 

PHILADELPHIA — Increasingly, researchers are suggesting that amyloid plaques and neurofibrillary tangles may be relatively late manifestations in the course of Alzheimer's disease (AD) pathology. Identifying earlier events in the development of AD remains a challenge. The laboratory of Virginia M.-Y. Lee, PhD, director of the Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, was the first, in 1993, to demonstrate unequivocally the presence of A-beta peptides — a hallmark of AD — inside neurons. But their role in Alzheimer's disease remained unclear.

"It was exciting when a 'triple transgenic' mouse model of AD was reported in 2003 to show robust staining of cells interpreted as A-beta peptides inside neurons," says Edward Lee, MD, PhD, assistant professor of Pathology and Laboratory Medicine, co-author on a study just out in the Journal of Neuroscience that questions the role of A-beta peptides in AD pathology.

The triple transgenic mouse has since become a popular model in AD studies, says Edward Lee. In these mice, A-beta molecules were detected before amyloid-plaque and neurofibrillary-tangle pathology showed up, suggesting that intraneuronal A-beta peptides lead to amyloid plaques, which then lead to neurofibrillary tangles inside neurons.

The Penn researchers examined the trajectory of neuronal inclusions over time using rigorous biochemical and genetic methods. Virginia Lee's group discovered a case of mistaken identity: The intraneuronal molecules appear not to be A-beta peptides themselves, but rather the A-beta amino acid sequence nested within its parent protein, the A-beta precursor protein. What's more, blocking A-beta peptides from forming in the triple transgenic mice had no effect on the formation of neurofibrillary tangles.

According to Virginia Lee, this finding is significant for Alzheimer drug development because it underlines the need for tau-focused drug discovery for AD since the idea that intracellular A-beta drives tangle formation was not substantiated. Therapies aimed at blocking A-beta production may not have any effect on tangle formation, which is consistent with human clinical trial data to date.

The role of intraneuronal A-beta in AD is still unclear, but these results have profound implications for studies of mechanisms of AD and for AD drug discovery since mouse models of presumptive intracellular A-beta are widely used, state the authors.

Please take a look at the Alzforum webinar about the debate on intraneuronal A-beta as a potential instigator of Alzheimer's disease: www.alzforum.org/res/for/journal/detail.asp?liveID=193

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.