RyR2 as a Target to Prevent Alzheimer's Symptoms in a Mouse Model of the Condition

Mouse models of Alzheimer's disease are quite artificial: mice, and indeed most mammals, do not naturally exhibit the relevant mechanisms underlying Alzheimer's disease, such as aggregation of amyloid-β. The details of the model become important in determining whether or not discoveries and interventions are relevant in anything other than the model. Thus one shouldn't become too excited by any small adjustment to cellular metabolism that appears to have profound effects on the progression of the condition in these models. Maybe it will be relevant to the human condition, but the odds are not good, looking at the history of this sort of thing. Still, the size of the effect in this case is quite interesting.

Researchers discovered that limiting the open time of a channel called the ryanodine receptor, which acts like a gateway to cells located in the heart and brain, reverses and prevents progression of Alzheimer's disease in animal models. A single RyR2 point mutation, which reduces RyR2 open time, prevents hyperexcitability, hyperactivity, memory impairment, neuronal cell death, and dendritic spine loss in an Alzheimer's disease mouse model.

Researchers also identified a drug, derived from the heart medication carvedilol, that interrupts the disease process by reducing the open type of the ryanodine receptor. The effect of giving the drug to animal models was remarkable: After one month of treatment, the memory loss and cognitive impairments in these models disappeared.

Previous research has shown that the progression of Alzheimer's disease is driven by a vicious cycle of the protein amyloid β (Aβ) inducing hyperactivity at the neuron level. However, the mechanism behind this wasn't fully understood nor were there effective treatments to stop the cycle. Here, the team used a portion of an existing drug used for heart patients, carvedilol, to treat mice models with Alzheimer's symptoms. "We treated them for a month and the effect was quite amazing. We couldn't tell the drug-treated disease models and the healthy models apart."

Link: https://libin.ucalgary.ca/news/research-team-discovers-breakthrough-potential-prevent-reverse-alzheimers

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Also...
https://www.sciencedaily.com/releases/2020/11/201102120039.htm
Date: November 2, 2020 Source: Wiley

Summary: A bacterium found among the soil close to roots of ginseng plants could provide a new approach for the treatment of Alzheimer's. Rhizolutin, a novel class of compounds with a tricyclic framework, significantly dissociates the protein aggregates associated with Alzheimer's disease both in vivo and in vitro, as reported by scientists.

'... Rhizolutin leads to clear dissociation of insoluble Aβ and tau aggregates. In cultures of neuronal and glial cells, rhizolutin was able to markedly reduce the inflammatory processes and cell death caused by Aβ. Rhizolutin was also able to significantly dissociate the Aβ plaques present in the brains of mice with Alzheimer's. The process seems to be similar to the removal of incorrectly folded proteins through immunotherapy.'

Posted by: Jones at November 3rd, 2020 1:31 AM
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