Home Medizin Seltene Genmutationen bei erblicher Alzheimer-Krankheit stören die Amyloidproduktion, wie eine Studie zeigt

Seltene Genmutationen bei erblicher Alzheimer-Krankheit stören die Amyloidproduktion, wie eine Studie zeigt

von NFI Redaktion

Research conducted by the University of Kansas on rare gene mutations that cause hereditary Alzheimer’s disease reveals that these mutations disrupt the production of a small sticky protein called amyloid.

Amyloid plaques, known to occur in the brain in Alzheimer’s disease, have long been considered responsible for the inexorable loss of neurons and cognitive decline. Using a model worm called C. elegans, commonly used in laboratories to study diseases at a molecular level, the research team concluded that the stalled process of amyloid production -; not the amyloid itself -; can lead to the loss of critical connections between nerve cells.

The research, led by Michael Wolfe, Mathias P. Mertes Professor of Medicinal Chemistry at KU, appears in the journal Cell Reports.

The research team focused on the rare inherited mutations, as these mutations occur in genes that encode proteins that produce amyloid.

„If we can understand what happens in this inherited form of the disease, where a single mutation can trigger it, that could be a clue to what is happening in all other cases.“


Michael Wolfe, Mathias P. Mertes Professor of Medicinal Chemistry at KU

These rare mutations are particularly devastating, as they result in the carrier developing Alzheimer’s at a middle age, and children of a mutation carrier have a 50% chance of inheriting the disease-causing mutation.

Wolfe stated that hereditary Alzheimer’s disease exhibits the same pathology, clinical presentation, and course of symptoms as the „common, typical variant“ of age-related Alzheimer’s disease.

„You see the same amyloid plaques in the inherited disease,“ he said. „We believe that these inherited mutations, though rare, are the key to the processes in the entire Alzheimer’s disease.“

Wolfe, who earned his Ph.D. at KU and returned to the university seven years ago for collaborative research opportunities, teamed up with Brian Ackley, Associate Professor of Molecular Biology at KU, whose lab specializes in research using the model worm C. elegans. The research team also included other KU staff as well as researchers in Beijing, China, and at Harvard Medical School.

Co-authors from the Department of Medicinal Chemistry at KU were Sujan Devkota, Vaishnavi Nagarajan, Arshad Noorani, and Sanjay Bhattarai; co-authors from the Department of Molecular Biosciences at KU were Ackley and Yinglong Miao; and co-authors from the Center for Computational Biology at KU were Hung Do and Anita Saraf. Additional co-authors from KU included Caitlin Overmeyer from the Graduate Program in Neurosciences and Justin Douglas from the Nuclear Magnetic Resonance Core Lab at KU. The KU personnel collaborated with Rui Zhou from Tsinghua University in Beijing and Masato Maesako from Harvard Medical School.

Wolfe said the discovery could pave the way for new approaches to Alzheimer’s therapy, and he hopes that other researchers and drug developers will pay close attention to his team’s findings.

„Our results suggest that a stimulator of the amyloid-producing enzyme is needed to restart blocked processes and address both issues: removing blocked protein complexes leading to the degeneration of nerve cell connections, and producing soluble forms of amyloid. This approach could address both contributing factors simultaneously.“

Source:

Journal reference:

Devkota, S., et al. (2024). Familial Alzheimer Mutations Stabilize Synaptotoxic γ-Secretase Substrate Complexes. Cell Reports. doi.org/10.1016/j.celrep.2024.113761.

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