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Mar 18, 2014

Key Advance Reported in Reducing Alzheimer's Plaque Formation

Key Advance Reported in Reducing Alzheimer's Plaque Formation

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  • Scientists at the University of Michigan say they have learned how to fix the Golgi complex that becomes fragmented in all Alzheimer’s patients and appears to be a major cause of the disease. They add that understanding this mechanism will help decode amyloid plaque formation in the brains of Alzheimer’s patients—plaques that kill cells and contribute to memory loss and other Alzheimer’s symptoms.

    The researchers also reported their discovery of the molecular process behind Golgi fragmentation and the development of two techniques to “rescue” the Golgi structure.

    “We plan to use this as a strategy to delay the disease development,” said Yanzhuang Wang, Ph.D., U-M associate professor of molecular, cellular, and developmental biology. “We have a better understanding of why plaque forms fast in Alzheimer’s and found a way to slow down plaque formation.”

    The paper (“Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production”) appears in an upcoming edition of the Proceedings of the National Academy of Sciences.

    Dr. Wang said scientists have long recognized that the Golgi becomes fragmented in the neurons of Alzheimer’s patients, but until now they didn’t know how or why this fragmentation occurred. The Golgi structure has the important role of sending molecules to the right places in order to make functional cells. When the Golgi becomes fragmented, molecules get sent to the wrong places or not sent at all.

    U-M researchers found that the accumulation of the Aβ peptide, the primary culprit in forming plaques that kill cells in Alzheimer’s brains, triggers Golgi fragmentation by activating an enzyme called cdk5 that modifies Golgi structural proteins such as GRASP65.

    “Aβ accumulation triggers Golgi fragmentation by activating cyclin-dependent kinase-5 (cdk5), which phosphorylates Golgi structural proteins such as GRASP65,” wrote the investigators. “Rescue of Golgi structure by inhibiting cdk5 or by expressing nonphosphorylatable GRASP65 mutants reduced Aβ secretion. Our study provides a molecular mechanism for Golgi fragmentation and its effects on APP trafficking and processing, suggesting Golgi as a potential drug target for AD [Alzheimer’s disease] treatment.”

    The next step is to see if Golgi fragmentation can be delayed or reversed in mice, according to Dr. Wang.



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