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Alzheimer's Research Provides New Way To Think Of The Disease

Alzheimer's Research

Researchers at Genentech Inc have published a new study in the journal Nature. The study provides some evidence that a normal process in which excess nerve cells and nerve fibers are pruned during prenatal development as a way to help sculpt healthy neuronal connections may become reactivated in the adult brain. When reactivated, the pruning may not always be as well refined as in the prenatal brain.

The axonal pruning and neuronal cell death is a natural process in the prenatal brain development, but its mechanistic basis remains poorly understood. The researchers are trying to understand this process.

The dominant view of Alzheimer's disease today is that it is caused by deposits of beta amyloid that accumulate in the brain, degrading and destroying nerve cells and robbing victims of their memory.

The researchers report that a beta-amyloid precursor protein (APP) and death receptor 6 (DR6, also known as TNFRSF21) activate a widespread caspase-dependent self-destruction program. This suggests that Alzheimer's is due to the activation of a pathway that is there for development purposes. It gives researchers a different way of looking at Alzheimer's disease."

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DR6 is required for both normal cell body death and axonal pruning in the developing brain. Neuronal cell body death requires caspase 3. The researchers found that axonal degeneration requires caspase 6, which is activated in a punctate pattern that parallels the pattern of axonal fragmentation.

DR6 is activated locally by an inactive surface ligand(s) that is released in an active form after trophic-factor deprivation,. The researchers identified the amyloid precursor protein (APP) as a DR6 ligand. Trophic-factor deprivation triggers the shedding of surface APP in a beta-secretase (BACE)-dependent manner.

The results indicate that APP and DR6 are components of a neuronal self-destruction pathway, and suggest that an extracellular fragment of APP, acting via DR6 and caspase 6, contributes to Alzheimer's disease.

The report is based on laboratory and mouse experiments, and further study is needed to validate the hypothesis.

For more information on Alzheimer's
Alzheimer's Associaiton

APP binds DR6 to trigger axon pruning and neuron death via distinct caspases; Nature 457, 981-989 (19 February 2009) | doi:10.1038/nature07767; Anatoly Nikolaev, Todd McLaughlin, Dennis D. M. O'Leary & Marc Tessier-Lavigne