An Alternative Way To Suppress Aβ In Alzheimer’s

Targeting TRPC6 instead of γ-secretase could be a promising way of treating Alzheimer’s disease, according to a study in mice.

AsianScientist (Dec. 4, 2015) – Researchers have found a potential way to suppress the production of a peptide critical to the development of Alzheimer’s disease, Beta-Amyloid (Aβ), as published in Nature Communications,

Over-production and accumulation of Aβ peptide is critical for the pathogenesis of Alzheimer’s disease. Generation of Aβ involves cleavage of amyloid precursor protein (APP) by γ-secretase, a protease known to cleave several substrates, including Notch.

However, attempts to treat Alzheimer’s disease patients by inhibiting γ-secretase activity have been disappointing. Finding specific modulators for γ-secretase could be another avenue to treat the disease.

Instead of directly inhibiting γ-secretase, researchers at the Institute of Neuroscience (ION), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, targeted a protein known as transient receptor potential canonical 6 (TRPC6).

They found that TRPC6 specifically interacts with APP but not with Notch, and that this interaction prevents APP binding to another protein known as presenilin 1. Overall, TRPC6 overexpression led to the inhibition of γ-secretase cleavage of APP, Aβ production, and plaque formation in the brains of mice. The authors found that even a fusion peptide derived from TRPC6 could reduced Aβ levels without affecting Notch cleavage.

These results demonstrated that preventing APP interaction with PS1 via TRPC6 could be a novel strategy to reduce Aβ formation. Finding molecule(s) with a similar function to TRPC6 or its peptide derivative may provide novel intervention candidates to treat Alzheimer’s disease patients, while circumventing the side effects induced by direct inhibition of γ-secretase activity.

The article can be found at: Wang et al. (2015) TRPC6 Specifically Interacts with APP to Inhibit its Cleavage by γ-Secretase and Reduce Aβ Production.


Source: Chinese Academy of Sciences; Photo: Shutterstock.
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