Study Suggests New Cause for Alzheimer's Disease

Finding goes against "plaque" and "tangles" theories

August 01, 2003

Public Affairs

Belmont, MA - The traditional battle lines that have been drawn in the area of Alzheimer's disease (AD) research are between the "bAPPtists" and the "Tauists." The bAPPtists believe that b-amyloid, a protein fragment derived from the amyloid precursor protein (APP) that accumulates in a brain with AD, is the smoking gun that causes neurons to die in this devastating disease that results in a loss of ability to learn and remember. The Tauists contend that the tangles found in the brains of individuals with AD, composed of a protein called tau, are at the root of the neurodegeneration that occurs in this disease.

However, a study published in the latest issue of the Journal of Neuroscience does an end-run around both of these camps and instead, suggests that the culprit is the APP itself. Led by Rachael L. Neve, PhD, director of the Molecular Neurogenetics Laboratory at McLean Hospital, and Donna L. McPhie, PhD, an instructor in Neve's lab, this study introduces a new model for studying AD. In the lab, Neve and McPhie informally call this model "Alzheimer's Disease in a Dish" because it allows them to study, in a dish of nerve cells, what happens in these cells as they undergo AD-like degeneration.

There are some forms of AD called familial AD (FAD) and they are caused by mutations in APP. Neve, McPhie and collaborators developed a novel method for introducing FAD mutations of APP into nerve cells in a dish. What they found is that the nerve cells that take up these mutations enter the cell cycle and undergo programmed cell death, or apoptosis. This is remarkable in that it mirrors exactly what has been shown recently to occur in AD brains. The authors demonstrate that normal APP binds to a protein kinase called p21 activated kinase 3 (PAK3) and activates it. Most likely, this interaction between APP and PAK3 normally is tightly regulated and is important in the normal brain for the maintenance of learning and memory functions. However, Neve, McPhie and collaborators show that FAD mutants of APP interact in an unregulated manner with PAK3 and this unregulated interaction pushes the nerve cells into the cell cycle, leading to the death of the cells by apoptosis.

In the normal brain, neurons are considered "terminally differentiated," which means that they are unable to enter the cell cycle. "These results are the first demonstration that pushing neurons into the cell cycle directly causes their death, and show for the first time that an abnormal activity of APP-as opposed to b-amyloid or tau-may cause neurodegeneration in AD," said Neve.

The results of this study indicate that APP 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.

"Our study suggests we can block the progression of AD by pushing this molecule back towards its life function," said Neve.

McLean Hospital, one of the nation's top-ranked psychiatric hospitals, maintains the largest research program of any private, U.S. psychiatric hospital. It is the largest psychiatric facility of Harvard Medical School, an affiliate of Massachusetts General Hospital and a member of Partners HealthCare.

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