2. Academic Validation
  3. The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease

The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease

  • Mol Psychiatry. 2025 Aug 26. doi: 10.1038/s41380-025-03143-5.
Jing Yan # 1 2,  Xiaohui Yang # 3,  Guilin Li # 4,  Omar A Ramirez 1,  Anna M Hagenston 1,  Zhe-Yu Chen 5 6 7,  Hilmar Bading 8 9
Affiliations

Affiliations

  • 1 Department of Neurobiology, Interdisciplinary Center for Neuroscience (IZN), Heidelberg University, Heidelberg, Germany.
  • 2 FundaMental Pharma GmbH, Heidelberg, Germany.
  • 3 Department of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.
  • 4 Research Center for Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China.
  • 5 Department of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China. zheyuchen@sdu.edu.cn.
  • 6 Research Center for Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China. zheyuchen@sdu.edu.cn.
  • 7 State Key Laboratory for Innovation and Transformation of Luobing Theory, Jinan, Shandong, P.R. China. zheyuchen@sdu.edu.cn.
  • 8 Department of Neurobiology, Interdisciplinary Center for Neuroscience (IZN), Heidelberg University, Heidelberg, Germany. bading@nbio.uni-heidelberg.de.
  • 9 Network Aging Research, Heidelberg University, Heidelberg, Germany. bading@nbio.uni-heidelberg.de.
  • # Contributed equally.
PMID: 40858778 DOI: 10.1038/s41380-025-03143-5
Abstract

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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