Today's Date: July 31, 2010

“The brain is the last frontier of science; there is no greater challenge”

--Dale Schenk, Chief Scientific Officer, a pioneer in Alzheimer's Immunotherapy

Resource Library

A Retrospective and Key Publications by Elan Scientists and Elan-Sponsored Research Teams

In 1992, scientists published the results of research they had begun six years earlier, when they initiated their work to discover and develop disease-modifying therapies for AD. The publication contained a landmark discovery: the beta-amyloid peptide is a normal bi-product of cultured neuronal cells and the brain, and can be readily detected in the laboratory setting.  These findings opened the way to initiate drug discovery efforts that were previously impossible. (Seubert et al. 1992 “Isolation and quantitation of soluble Alzheimer’s ß-peptide from biological fluids." Nature 359:325-27).

In 1995, scientists characterized and identified potential characteristics of a mouse model that developed Alzheimer-type, beta amyloid-containing plaques, mimicking many aspects of Alzheimer’s disease-like neuropathology, and making it possible to test compounds to be considered for the clinic. This model was termed the PDAPP mouse. (Games et al. “Alzheimer-type neuropathology in transgenic mice over-expressing V717F beta-amyloid precursor protein.” A letter in Nature, February 9, 1995, 373:523-527.)

In 1999, Elan scientists published a key paper that described amyloid-beta experiments with the PDAPP mouse model and the discovery that immunization with amyloid-beta could treat and prevent the disease pathology in this model.  This important discovery had direct application to AD: it introduced the scientific community to the idea that one could generate antibodies that target a brain disease.  This research helped shaped the direction of one of Elan’s key research avenues in AD, and in 2004, together with Wyeth laboratories, Elan began a Phase I clinical trial with a humanized antibody to beta-amyloid in an effort to passively transfer anti-amyloid antibodies to AD patients. (Schenk et al: “Immunization with amyloid-beta attenuates Alzheimer’s disease-like pathology in the PDAPP mouse.” Nature 400: 173-177, 1999.)

Other key publications regarding Elan’s immunotherapeutic approach to treating AD include:

  • Bard et al. “Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.” 2000. Nature Medicine 6: 916-919.
  • Schenk, Dale. “Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginning.” 2002. Nature Reviews Neuroscience 3: 824-828.
  • Bard et al. “Epitope and isotype specificities of antibodies to beta-amyloid peptide for protection against Alzheimer's disease-like neuropathology.” 2003 Proceedings of the National Academy of Sciences of the United States of America 100: 2023-2028. 

Also in 1999, Elan scientists published their discovery that beta secretase plays a critical role in the beta-amyloid hypothesis, and researchers are currently aggressively pursuing this important potential therapeutic target for AD. (Sinha et al. “Purification and cloning of amyloid precursor protein beta-secretase from human brain.” Nature 402: 537-540, 1999).

Further important research which confirmed beta secretase as a potential disease-modifying therapeutic target for AD was published in 2001 (Roberds SL et al. “BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics.” Human Molecular Genetics 10: 1317-1324, 2001).

In 2001 Elan scientists published their findings that gamma secretase also plays a key role in the beta amyloid hypothesis, and researchers are also currently pursuing this potential disease-modifying therapeutic target for AD. (Dovey et al. “Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.” Journal of Neurochemistry 76: 173-181, 2001).

In 2003, two leading AD researchers presented a comprehensive overview of worldwide Alzheimer’s research and the current understanding of the beta-amyloid hypothesis to date. (Please refer to Schenk, D. and Selkoe, D. “Alzheimer’s Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics.” Annual Review of Pharmacology and Toxicology, April 2003, Vol. 43: 545-584.)

For almost two decades, Elan’s achievements have been critical to the scientific community’s understanding of the neuropathology of AD. Today, Elan continues to be at the forefront of pursuing disease-modifying therapies for this devastating disease.