Alzheimers Pathology

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.
One of the mysteries of AD has been the normal function of the amyloid precursor protein (APP) which is concentrated at the synapse. Even though the amyloid plaques which have been viewed as a hallmark sign of AD result from APP, it seems unlikely that AD is simply a buildup of misprocessed APP . In a recent study, scientists from the Buck Institute and the CNRS (Centre Nationale de la Recherche Scientifique) show that APP binds to netrin-1, a protein that helps to guide axons.

When netrin-1 was given to mice that have a genetic mutation for Alzheimer’s disease, their symptoms were reversed. These results suggest that the long-held belief that AD is caused by neuronal damage inflicted by the amyloid plaques may be wrong; instead, it is beginning to appear that the disease stems from an imbalance between the normal making and breaking of synapses in the brain, with netrin-1 supporting synapse formation and the APP causing breaking the connections.

In their research, not only did the netrin-1 binding to APP keep the neurons alive and connected, but it also downregulated the production APP itself.

Reference: Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production. Lourenço et al. Cell Death Differ. 2009 May;16(5):655-63.

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