Amyloid Precursor Protein Linked to Alzheimer's Disease Mitochondrial Damage

Mitochondrial dysfunction in neurons, which typifies Alzheimer's disease, may be at least partially due to the interaction of a mitochondrial protein with amyloid precursor protein (APP).

A paper published in the June 2010 issue of the European Journal of Neuroscience described the discovery of the link between AAP and the mitochondrial protein NIPSNAP1 (4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1).

First author Dr. Hemachand Tummala, assistant professor of pharmaceutical sciences at South Dakota State University (Brookings, USA), explained, "In Alzheimer's disease, there is a protein involved called APP, amyloid precursor protein. If this protein is mutated, it causes early onset Alzheimer's disease. We do not know exactly what this protein does. One thing is very well documented in Alzheimer's disease; mitochondria in a cell are damaged. They lose their function. This happens long before the appearance of symptoms. So there is a theory that mitochondria play a big role in the disease progression.”

The authors reported that the interaction between APP and NIPSNAP1 was confirmed both in transiently transfected COS7 cells and in the mouse brain, where NIPSNAP1 is expressed at a high level. They demonstrated that NIPSNAP1 was targeted to the mitochondria via its N-terminal targeting sequence, and interacted with mitochondrial chaperone translocase of the outer membrane. Mitochondrial localization of NIPSNAP1 appeared to be critical for its interaction with APP, and overexpression of APP appeared to disrupt NIPSNAP1 mitochondrial localization.

"This work is still at the preliminary stages. If everything goes well, if we establish the link, this may in the future become a new therapeutic target,” said Dr. Tummala. "Our hypothesis is that mitochondria are damaged long before the appearance of symptoms. If you could stop that mitochondrial damage, it may slow down neuronal death and halt the disease progression. But that would be far in the future, not now.”

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South Dakota State University