Identification of Contactins and L1-CAMs as ligands for the Amyloid Precursor Protein

Summary Approximately 24 million people worldwide have dementia of which the majority (~60%) is due to Alzheimer’s; by 2040, it is projected that this figure will have increased to 81 million. The drugs currently on the market, such as cholinesterase inhibitors, reduce the cognitive symptoms of Alzheimer’s disease (memory, language, judgment, and other thought processes) and may improve patient’s quality of life but they do not cure the disease.

Applications New insights into the mechanism of Alzheimer’s disease are reported here. New therapeutic targets are identified that could be used to develop novel pharmaceutical compositions.

Alzheimer’s disease is a neurodegenerative disease that is morphologically characterized by the presence in the brain of intracellular tangles and extracellular plaques. The beta-amyloid precursor protein (APP) was originally identified as the source of the b-amyloid peptide (Ab), a major component of the plaques seen in the brains of patients with Alzheimer’s disease. APP is a transmembrane protein with a large extracellular fragment and a relatively small intracellular domain. APP can be cleaved by b- and g secretases to release the large extracellular fragment; the remaining transmembrane domain generates Ab. The accumulation of Ab results in the formation of plaques, which ultimately lead to neuronal dysfunction and death. The normal functions of APP are not well understood. A number of extracellular binding partners for APP have been identified (including metal ions, heparin, collagen, F-spondin, Notch, Nogo receptor) but the functional significance of these interactions remain unclear.

The Flanagan lab has identified Contactins and L1-CAMs glycoproteins as binding partners of APP. Functional assays revealed regulatory effects of Contactins and L1-CAMs on APP processing. We anticipate that Contactins and L1-CAMs could be used to inhibit APP processing to Ab or modulate the biological function of APP. The methods developed in these studies can also be used to identify other compounds that interfere with these pathways to ultimately treat or prevent Alzheimer’s disease.

This discovery has various implications in the treatment and prevention of neurodegenerative diseases. We anticipate that it can be used to develop:
- Pharmaceutical preparations based on Contactins or L1-CAMs against Alzheimer’s disease;
- Screening assays to find small-molecule drugs against Alzheimer’s disease;
- Treatments to other diseases such as CRASH syndrome (L1 deficiency) and 3p deletion syndrome (contactin deficiency).


Harvard has filed a patent (Serial 60/839,114) in August 2007. For Further Information Please Contact the Director of Business Development Katie Gordon Email: katherine_gordon@hms.harvard.edu Telephone: (617) 432-0920

Inventor(s): Flanagan, John G

Type of Offer: Licensing



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