Our work on Alzheimer's disease focuses on the genetics and biology of molecules that have been implicated in the pathogenesis of this disease. We have isolated the gene for the Alzheimer amyloid protein precursor which is on chromosome 21 and is very likely the key player in the death of nerve cells in Alzheimer's disease. We are using an array of genetic techniques to define the genetic events that lead to the profound neurodegeneration displayed in Alzheimer's disease. In addition, we developed an in vivo animal model for Alzheimer's disease that is based on our finding that the carboxyterminal 100 amino acids of the amyloid protein precursor (C100) is neurotoxic. Transgenic mice expressing this carboxyterminal fragment of the amyloid protein precursor in the brain display amyloid deposition, synaptic degeneration, and cognitive impairment, all of which are characteristic of Alzheimer's disease. Most recently, we have identified binding proteins for the C100 fragment that mediates the neurodegeneration caused by C100. Our work with these proteins has established that C100 activates a signal transduction pathway that causes entry of neurons into the cell cycle and their subsequent death by apoptosis. This probably is the means by which neurons die in Alzheimer's disease.

Key words: Alzheimer's disease, amyloid, neurodegeneration, molecular biology.

Grant Support: NINDS: RO1 NS28965, Molecular Biology of Alzheimer Disease Neurodegeneration. Awards: Metropolitan Life Foundation, Johnson & Johnson Focused Giving Award.

Project Site: Department of Psychiatry: Molecular Neurogenetics Laboratory, McLean Hospital.

Project Director and Contact Person: R.L. Neve, Molecular Neurogenetics Laboratory, McLean Hospital, 115 Mill St., Belmont, MA 02115. Tel: (617) 855-2413. FAX: (617) 855-3793.

Training Opportunities: Currently two postdoctoral fellows are in our laboratory. One postdoctoral position is available.

Tanzi RE, Gusella JF, Watkins PC, Bruns GAP, St. George-Hyslop P, Van Keuren M, Patterson D, Pagan S, Kurnit DM, Neve RL. The amyloid b protein gene: cDNA cloning, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 1987; 235:880-884.

Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL. Neurotoxocity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 1989; 245: 417-420.

Kammesheidt A, Boyce FM, Spanoyannis AF, Cummings BJ, Ortegon M, Cotman CW, Vaught JL, Neve RL. Amyloid deposition and neuronal pathology in transgenic mice expressing the carboxyterminal fragment of the Alzheimer amyloid precursor in the brain. Proc Natl Acad Sci USA, 1992; 89:10857-10861.

Chen Y, McPhie DL, Hirschberg J, Neve RL. The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons. J Biol Chem 2000; 275:8929-8935.

McPhie DL, Golde T, Eckman CB, Yager D, Younkin SG, Neve RL. The b -secretase cleavage product of the amyloid precursor protein mediates neuronal apoptosis caused by familial Alzheimer's disease mutations. Mol Brain Res 2001; 97:103-113.