Success in Reversing Dementia in Mice and Human Clinical Trials in 2022

Researchers have identified a new treatment candidate that appears to not only halt neurodegenerative symptoms in mouse models of dementia and Alzheimer’s disease, but also reverse the effects of the disorders.

The team, based at Tohoku University, published their results on June 8 in the International Journal of Molecular Sciences. The treatment candidate has been declared safe by Japan’s governing board, and the researchers plan to begin clinical trials in humans in the next year.

“There are currently no disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer’s disease, Lewy body dementia, Huntington disease and frontotemporal dementia in the world,” said paper author Kohji Fukunaga, professor emeritus in Tohoku University’s Graduate School of Pharmaceutical Sciences. “We discovered the novel, disease-modifying therapeutic candidate SAK3, which, in our studies, rescued neurons in most protein-misfolding, neurodegenerative diseases.”

In comparison, Aduhelm, the Alzheimer’s drug recently approved by the U.S. Food and Drug Administration, reduces the number of amyloid plaques in the brain, but it is not yet known if the amyloid reduction actually prevents further cognitive or motor decline in patients. According to Fukunaga, SAK3 helps destroy amyloid plaque – at least in mice.

SAK3 also helps manage the destruction of misfolded alpha-synuclein. Normal alpha-synuclein helps regulate neurotransmitter transmission in the brain. The protein can misfold and aggregate, contributing to what researchers suspect may be an underlying cause of neurodegenerative symptoms. This aggregation can also lead to the loss of dopamine neurons, which help with learning and memory.

“We found that chronic administration of SAK3 significantly inhibited the accumulation of alpha-synuclein in the mice,” Fukunaga said, noting that the mice received a daily oral dose of SAK3.

According to Fukunaga, SAK3 enhances the activity of the system that identifies and destroys misfolded proteins. In neurodegenerative diseases, this system is often dysfunctional, leaving misfolded proteins to muck up the cell’s machinery.

“SAK3 is the first compound targeting this regulatory activity in neurodegenerative disorders,” Fukunaga said. “SAK3 administration promotes the destruction of misfolded proteins, meaning the therapeutic has the potential to solve the problems of diverse protein misfolding diseases such as Parkinson’s disease, Lewy body dementia and Huntington disease, in addition to Alzheimer’s disease.”

International Journal of Molecular Sciences- T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model

Abstract
Lewy bodies are pathological characteristics of Lewy body dementia (LBD) and are composed of α-synuclein (α-Syn), which is mostly degraded via the ubiquitin–proteasome system. More importantly, 26S proteasomal activity decreases in the brain of LBD patients. We recently introduced a T-type calcium channel enhancer SAK3 (ethyl-8-methyl-2,4-dioxo-2-(piperidin-1-yl)- 2H-spiro[cyclopentane-1,3-imidazo [1,2-a]pyridin]-2-ene-3-carboxylate) for Alzheimer’s disease therapeutics. SAK3 enhanced the proteasome activity via CaMKII activation in amyloid precursor protein knock-in mice, promoting the degradation of amyloid-β plaques to improve cognition. At this point, we addressed whether SAK3 promotes the degradation of misfolded α-Syn and the aggregates in α-Syn preformed fibril (PFF)-injected mice. The mice were injected with α-Syn PFF in the dorsal striatum, and SAK3 (0.5 or 1.0 mg/kg) was administered orally for three months, either immediately or during the last month after injection. SAK3 significantly inhibited the accumulation of fibrilized phosphorylated-α-Syn in the substantia nigra. Accordingly, SAK3 significantly recovered mesencephalic dopamine neurons from cell death. Decreased α-Syn accumulation was closely associated with increased proteasome activity. Elevated CaMKII/Rpt-6 signaling possibly mediates the enhanced proteasome activity after SAK3 administration in the cortex and hippocampus. CaMKII/Rpt-6 activation also accounted for improved memory and cognition in α-Syn PFF-injected mice. These findings indicate that CaMKII/Rpt-6-dependent proteasomal activation by SAK3 recovers from α-Syn pathology in LBD.

SOURCES – Xu, J.; Kawahata, I.; Izumi, H.; Fukunaga, K. T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model. Int. J. Mol. Sci. 2021, 22, 6185. https://doi.org/10.3390/ijms22126185, Tohoku University
Written By Brian Wang, Nextbigfuture.com

31 thoughts on “Success in Reversing Dementia in Mice and Human Clinical Trials in 2022”

  1. I concur, but carried to the logical extreme, that would pretty much involve staying healthy and robust until the second you die, in which case, why are you dying?

    This is not aimed at you at all but every time I hear someone say they'd rather just "grow old gracefully" I want to grab them and drag them through some hospices and geriatric wards.

    There is nothing graceful about having to wear a bag for your urine strapped to your leg, not being able to walk around your own home, not being able to live in your own home, needing assistance to go to the bathroom, being eaten alive by painful cancers, gradually losing your mind, or a myriad number of other indignities that old age forces upon us.

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  2. Future generations should appreciate that all the immortal mice we are going to create for them will still be in their right minds.

    But yes, wonderful news if it works out for us. An Alzheimer's diagnosis is one of those few things I find so horrible that getting one would likely make me say my goodbyes and disappear off the grid . . . before it got to the point where I could neither make that choice nor carry it out.

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  3. I don't understand is why it takes so long to get to human trials. I am sure if someone is on the verge of death they would give an experimental treatment a go.

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  4. If that happened quickly, it would be less scary.

    But the disease takes its time and let's you enjoy all the ride towards disintegration of the self.

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  5. If it turns out that the drug helps humans even partially, I have no doubt the Nobel will come out in the same year that the preliminary human studies come out.

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  6. Well, not necessarily. As you get down to the molecular level, and the level of things happening inside cells, every process starts to look reversible, or at least pseudo-reversible.

    What do I mean by this? It's not so much irreversible process X just happens and accumulates until a disease or death occurs. It's more like: process X happens, and another process Y repairs the damage. But for every 100 times X takes place, the Y repairs only happen 99 times. So it slowly accumulates over time, but not because it can't be fixed. Rather, the process that would fix it, can't keep up.

    It would therefore only take a slight increase in the repair rate, or a slight decrease in the damage rate, to suddenly see the damage reverse itself over time.

    This is counterintuitive because it doesn't make any sense at the macro level. For example, if you lose an arm, it ain't growing back. But at the subcellular level, it's more of a numbers game. It's a war of attrition rather than a decisive battle.

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  7. Bypassing if the lymph node massage helps Alzheimers (seems useful for general health) I will agree with you and say that anyone who only agrees to The Official Truth will be very hard very far behind the curve.

    Good example would be low fat diets vs The State Sponsored Truth of high carb diets/food pyramid.

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  8. And, it would be a complication, not a cause. The formation of the plaques is before this is a problem. And, not expected all the time, either. Unless, of course, it IS the (unlikely) cause.

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  9. If you always wait for some bit of knowledge to become mainstream and sanctioned, you'll always be behind the curve, by definition. It's the willingness to be open minded and think for yourself that gets you to interesting intellectual frontiers. Yes, you risk being wrong. But that's life.

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  10. I don't know, but somewhat related: I have heard that people who sleep on their sides fare better than people who sleep on their back. There does seem to be some kind of draining of waste that can take place. Of course, people will swear up and down it's an old wives' tale, but I've heard enough anecdotes to think there might be a kernel of truth to it.

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  11. It would remove the already created waste product. So more can follow. Do you know what a "?" is?

    edit: search "lymph massage alzheimer's" for much info. Then, you can answer the question perhaps. Like the people who can without doing all that work, that I asked.

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  12. Okay, you've "heard"–please provide your source.
    This is about misfolded molecules _inside_ neurons.

    If you are getting a massage to your neck that can _burst_ cells in the brain to release the damaged proteins, I don't think you are going to survive that.

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  13. I know a lot of people sick around me , this really hard for their family, if this is working for human, that will be a great step for them

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  14. I've heard that massage of the neck lymph nodes can help *drain* the plaque stuff out, so to speak. May help if this treatment produces even more waste product????

    Reply

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