Molecular Approaches to Down's Syndrome and Alzheimer's Disease

In 1984 and 1985, Kurnit and coworkers reported that Down's syndrome cells from developing lungs and hearts are more adhesive to each other than are the cells of normal controls (Am. J. Med. Gen., 1985; Proc. Natl. Acad. Sci., 1984). They also showed by computer simulations how such increased adhesiveness could result in the congenital lung and heart defects that are characteristically seen in Down's syndrome. Subsequent work in this IDDRC has discovered families of cell adhesion proteins important in neural development. An important relationship between Alzheimer's disease and Down's syndrome was established with the demonstrations that patients with Down's syndrome suffer a progressive dementing illness in adult life and that the pathological characteristics of this illness are similar to those that occur in Alzheimer's disease. The core of the characteristic pathological change is the formation of plaques composed of the Beta-amyloid peptide. This similarity between Down syndrome and Alzheimer’s disease focused attention on chromosome 21. Dr. Rachel Neve et al., formerly in the Genetics Program of this IDDRC, reported the isolation and location of the Beta-amyloid gene on chromosome 21 in a paper in Science in 1987. In later experiments, reported in Science in 1989, Dr. Bruce Yankner of this Center showed that a fragment of the amyloid precursor protein (Beta?-amyloid) is toxic to neurons grown in tissue culture. This polypeptide appears to have a major role in the pathogenesis of the Alzheimer’s disease process. Dr. Yankner subsequently discovered that the fibrillar form of Beta-amyloid, as found in mature plaques in Alzheimer’s disease and in Down’s syndrome, and not the amorphous form is neurotoxic, and that microinjection of the fibrillar form into monkey brain results in Alzheimer-type neuronal injury.  Dr. Yankner’s research then delineated the mechanism of amyloid toxicity and has raised the possibility of a rational therapeutic approach to therapy. In recent years Dr. Yankner has amplified these observations, establishing a crucial link between Beta?-amyloid neurotoxicity and the toxicity of the related compound amylin to the Beta-cells of pancreatic islets and therefore diabetes, and has extended his studies in important ways to provide insight into the dementia of Down syndrome.