TRPM7 kinase stimulates the degradation of amyloid-β and prevents cognitive impairments in mouse models of Alzheimer's disease

As outlined in my book on neurodegeneration in Chapter 2.3.2, amyloid is reduced by Aβ-degrading enzymes, which include insulin-degrading enzyme (IDE), neprilysin (NEP), angiotensin-converting enzyme (ACE), and various matrix metalloproteinases (MMPs). MMPs are zinc-containing endopeptidases that play a role in Aβ degradation and synaptic functions.

In Alzheimer’s patients, mRNA levels of MMP14 are elevated in the temporal cortex. Protein expression of MMP14 is increased in the hippocampi of 5XFAD mice, an experimental animal model of Alzheimer’s disease. An increase in MMP14 expression promotes Aβ degradation in astrocytes. Therefore, the Aβ-degrading enzyme MMP14 could play a role in the pathology of Alzheimer’s disease and represent a potential therapeutic approach for reducing Aβ plaques, protecting synapses, and preventing memory deficits.

The 'Transient Receptor Potential Melastatin-like 7 protein' (TRPM7) is a unique ion channel that contains a kinase domain at its C-terminus. When cleaved, this domain is translocated to the nucleus to regulate various cellular functions. In the mammalian brain, the cleaved kinase domain is important for synaptic plasticity, and thus for learning and memory.

As shown last year in Science Signaling by the research groups of Wei Li and Nashat Abumaria at Fudan University in Shanghai, China, TRPM7 kinase activity is crucial for Aβ degradation. They demonstrated that TRPM7 expression is significantly reduced in hippocampal tissue samples from AD patients as well as in two Alzheimer's mouse models (APP/PS1 and 5XFAD). In cultures of hippocampal neurons from mice, overexpression of TRPM7 or its functional kinase domain M7CK prevented exogenously induced Aβ synapse loss. In contrast, this neuroprotective effect was not achieved by overexpression of the functional ion channel portion or a TRPM7 mutant lacking kinase activity.

Overexpression of M7CK in the hippocampus of young and old 5XFAD mice prevented memory deficits, synapse loss, and Aβ plaque accumulation. M7CK interacted with the metalloprotease MMP14 and activated it to promote Aβ degradation. The authors correctly conclude that TRPM7 inhibition in Alzheimer’s patients could represent a potential therapeutic strategy.

Reference:

Zhang S, Cao F, Li W, Abumaria N (2023) TRPM7 kinase activity induces amyloid-β degradation to reverse synaptic and cognitive deficits in mouse models of Alzheimer’s disease. *Science Signaling* 16:eade6325.

Image credit: ChatGPT