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TRPM7 kinase activity induces amyloid-β degradation to reverse synaptic and cognitive deficits in mouse models of Alzheimer's disease.
- Source :
- Science Signaling; 7/11/2023, Vol. 16 Issue 793, p1-17, 17p
- Publication Year :
- 2023
-
Abstract
- Altered abundance or activity of the dual-function transient receptor potential melastatin-like 7 (TRPM7) protein is implicated in neurodegenerative disorders, including Alzheimer's disease (AD). Toxic aggregation of amyloid-β (Aβ) in neurons is implicated in AD pathology. Here, we found that the kinase activity of TRPM7 is important to stimulate the degradation of Aβ. TRPM7 expression was decreased in hippocampal tissue samples from patients with AD and two mouse models of AD (APP/PS1 and 5XFAD). In cultures of hippocampal neurons from mice, overexpression of full-length TRPM7 or of its functional kinase domain M7CK prevented synapse loss induced by exogenous Aβ. In contrast, this neuroprotection was not afforded by overexpression of either the functional ion channel portion alone or a TRPM7 mutant lacking kinase activity. M7CK overexpression in the hippocampus of young and old 5XFAD mice prevented and reversed, respectively, memory deficits, synapse loss, and Aβ plaque accumulation. In both neurons and mice, M7CK interacted with and activated the metalloprotease MMP14 to promote Aβ degradation. Thus, TRPM7 loss in patients with AD may contribute to the associated Aβ pathology. Editor's summary: The abundance of the dual-function ion channel and kinase TRPM7 is decreased in postmortem brain samples from patients with Alzheimer's disease (AD). Zhang et al. uncovered a pathological role for loss of TRPM7 in AD. In mice modeling amyloid-β–induced pathology, synapse formation and cognitive function were restored in aged mice and preserved in pre-symptomatic, younger mice upon overexpression of the kinase portion of TRPM7 (called M7CK). M7CK directly activated the protease MMP14, which promoted amyloid-β degradation and clearance. The findings may provide a mechanistic link between TRPM7 loss and amyloid pathology in AD patients.–Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19450877
- Volume :
- 16
- Issue :
- 793
- Database :
- Complementary Index
- Journal :
- Science Signaling
- Publication Type :
- Academic Journal
- Accession number :
- 164816622
- Full Text :
- https://doi.org/10.1126/scisignal.ade6325