Elucidating the role of TRPM7 chanzyme and its therapeutic potential in neuroinflammation of Alzheimer’s disease

Project: Research project

Project Details

Description

Alzheimer’s disease (AD) is the most common form of dementia that is currently uncurable. Although drugs target pathological hallmarks including beta-amyloid (Aβ) or hyperphosphorylated tau have been developed, none of them obtains strong evidence of efficacy in the clinical trials. This unsatisfactory outcome urged us to identify novel pathogenic targets that may help future anti-AD drug development. There is evidence showing persistent glial activation in AD brain and Aβ plaques are surrounded by reactive microglia that may suggest neuroinflammation is playing a pivotal role in the pathogenesis and progression of AD. However, the molecular mechanism leading to persistent neuroinflammation in AD is largely unknown.

Our preliminary data identified that the transient resistant potential protein subfamily M, member 7 (TRPM7) is highly expressed in reactive microglia which surround the Ab plaques in the AD mouse (5xFAD) brain. Interestingly, after the 5xFAD mice were treated with TRPM7 inhibitor carvacrol, the amount of Ab plaques and reactive microglia level were significantly reduced. It also improved memory function in 5xFAD as measured by the Morris water maze indicating the inhibition of TRPM7 could be a therapeutic strategy against AD. Mechanistically, we observed microglial activation upon inflammatory stimulation by LPS or Ab oligomers (Aβo) in vitro which can be prevented by carvacrol or siRNA against the TRPM7. We also found inflammatory stimulation evoked Ca2+ influx into microglial cells through the TRPM7 channel and its kinase domain translocated to the nucleus upon stimulation. These LPS- and Aβo-mediated microglia activation can be abolished by TRPM7 inhibitors carvacrol and FTY720. Intriguingly, we found that modulation of TRPM7 activity could regulate pro-inflammatory microglia transit into anti-inflammatory. Altogether, we hypothesize the TRPM7 chanyme is a key regulator for modulating ADassociated neuroinflammation, and drugs targeted on the TRPM7 could serve as a therapeutic agent for AD treatment.

In this study, we will employ molecular, cellular, and transgenic animal approaches:
(1) to consolidate the roles of TRPM7 chanzyme in the neuroinflammation of AD; (2) to elucidate the regulation of TRPM7 chanzyme in microglia phenotype transition; and,
(3) to evaluate the role and efficacy of TRPM7 inhibition in mitigating AD-associated neuroinflammation in vivo.

Results from this study will broaden our knowledge of the roles of TRPM7 in neuroinflammation. The identification of TRPM7 as a key regulator of AD-associated neuroinflammation will provide clues to new drug development. Ultimately, we anticipate therapeutic agents targeting the microglial TRPM7 would be an effective cure for AD.
StatusActive
Effective start/end date1/10/2330/09/26

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