The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer’s disease
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, characterized by cognitive decline and neuronal degeneration. The formation of amyloid β plaques and neurofibrillary tangles are key morphological features of AD pathology. However, the specific molecules responsible for the...
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| Hauptverfasser: | , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2025
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| In: |
Molecular psychiatry
Year: 2025, Pages: 1-14 |
| ISSN: | 1476-5578 |
| DOI: | 10.1038/s41380-025-03143-5 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41380-025-03143-5 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41380-025-03143-5 
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| Verfasserangaben: | Jing Yan, Xiaohui Yang, Guilin Li, Omar A. Ramirez, Anna M. Hagenston, Zhe-Yu Chen and Hilmar Bading |
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| 520 | |a Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, characterized by cognitive decline and neuronal degeneration. The formation of amyloid β plaques and neurofibrillary tangles are key morphological features of AD pathology. However, the specific molecules responsible for the cell destruction triggered by amyloid β and tau proteinopathies in AD has not yet been identified. Here we use the 5xFAD mouse model of AD to investigate the role of a recently discovered death signaling complex which consists of the extrasynaptic N-methyl-D-aspartate receptor (NMDAR) and the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 death complex is responsible for toxic signaling of glutamate, which has been implicated in AD pathogenesis. We detected an increase in NMDAR/TRPM4 death complex formation in the brains of 5xFAD mice. This increase was blocked by the oral application of FP802, a small molecule TwinF interface inhibitor that can disrupt and thereby detoxify the NMDAR/TRPM4 death complex. FP802 treatment prevented the cognitive decline of 5xFAD mice assessed using a series of memory tasks. It also preserved the structural complexity of dendrites, prevented the loss of synapses, reduced amyloid β plaque formation, and protected against pathological alterations of mitochondria. These results identify the NMDAR/TRPM4 death complex as a major promoter of AD disease progression, amplifying potentially self-perpetuating pathological processes initiated by amyloid β. TwinF interface inhibitors offer a novel therapeutic avenue, serving as an alternative or complementary treatment to antibody-mediated clearing of amyloid β from AD brains. | ||
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