MAILMAN RESEARCH CENTER

Molecular Neurogenetics Laboratory

Although we've learned a great deal about Alzheimer's disease (AD) in the last decade, we still do not understand what causes the nerve cell death that leads to the loss of the ability to learn and remember in the disease. We have developed a novel model for AD ("Alzheimer's disease in a dish") that is allowing us to find out what happens in a nerve cell as it undergoes AD-like degeneration. Our results indicate that the amyloid precursor protein (the source of the amyloid that accumulates in AD brain) controls both life and death processes in the brain. In AD, this molecule is pushed towards its death function, and kills nerve cells involved in learning and memory. These results suggest that we can block the progression of AD by pushing this molecule back towards its life function.

Collaborations

The Neve lab is a component of a Conte Neuroscience Center Grant awarded to Dr. Eric J. Nestler in the Department of Psychiatry at the University of Texas Southwestern Medical Center in Dallas, Texas. Funded by the National Institute of Mental Health (NIMH), this award supports collaborative research on mental health and includes scientists from numerous universities around the United States. The specific purpose of this grant is to study the molecular basis of mood regulation.

Research Support

Recent Updates

Molecular Neurogenetics Laboratory investigators have developed a novel cultured cell model for Alzheimer's disease (AD). This model allows them to study what happens in a nerve cell as it undergoes Alzheimer's-like degeneration, offering a possible way for scientists in the future to block AD's destructive effects. Early results indicate that the amyloid precursor protein (the source of the amyloid that accumulates in an AD brain) is involved in both life and death processes of cells. In AD, this molecule expresses its destructive function, and kills nerve cells involved in learning and memory. Redirecting the cellular function of this molecule back toward its more positive functions might someday be employed to block AD.

Personnel

Rachael L. Neve, Ph.D., Associate Professor in Psychiatry, Harvard Medical School; Director, Molecular Neurogenetics Laboratory (e-mail)
Donna L. McPhie, Ph.D., Instructor in Psychiatry, Harvard Medical School (e-mail)
Daphna Laifenfeld, Ph.D - Postdoctoral Fellow (e-mail)
Tracey Reihle - Technical Research Assistant (e-mail)
Dawn Morrissey - Executive Assistant & Lab Manager Molecular Neurogenetics Laboratory, Executive Assistant to Cellular Neurobiology Laboratory (e-mail)

Representative Publications

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; 275:8929-35.
McPhie DL, Golde T, Eckman CB, Yager D, Younkin SG, Neve RL. The beta-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.
McPhie DL, Coopersmith R, Hines-Peralta A, Chen Y, Ivins KJ, Manly SP, Kozlowski MR, Neve KA, Neve RL. DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J Neurosci 2003; 23:6914-6927.
Chen Y, Liu W, McPhie DL, Hassinger L, Neve RL. APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer’s disease brain. J Cell Biol 2003; 163:27-33.
Herrup K, Neve R, Copani A, Ackerman S. Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci 2004; 24:9232-9239.
Neve RL, Nestler EJ, Neve KA, Carlezon WA. Use of herpes simplex virus amplicon vectors to study brain disorders. BioTechniques 2005; 39:381-391.
Neve RL, McPhie DL. Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis. Biochimica Biophysica Acta 2007; 1772:430-437.
Laifenfeld D, McPhie DL, Patzek LJ, Chen Y, Levites Y, Cataldo AM, Neve RL. Rab5 mediates an APP signaling pathway that leads to apoptosis. J Neurosci 2007; 27(27):7141-53.