Credit: National Institute on Aging, NIH
Researchers at Tohoku University in Japan have identified a new treatment candidate that seems to not only halt but partially reverse neurodegenerative symptoms in mouse models of dementia and Alzheimer’s disease.
Kohji Fukunaga, professor emeritus in Tohoku University’s Graduate School of Pharmaceutical Sciences and paper author, said: “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. We discovered the novel, disease-modifying therapeutic candidate SAK3, which, in our studies, rescued neurons in most protein-misfolding, neurodegenerative diseases.”
In previous work, the team found that the SAK3 molecule – the base structure of which is found in the enhancement of T-type Ca2+ channel activity – apparently improved memory and learning in a mouse model of Alzheimer’s disease.
SAK3 enhances the function of a cell membrane channel thereby promoting neuronal activity in the brain. Typically, SAK3 promotes neurotransmitter releases of acetylcholine and dopamine — neurotransmitters which are lowered in Alzheimer’s disease and Lewy body dementia. The Ca2+ channel enhancement is thought to trigger a change from resting to active in neuronal activity. When the Ca2+ channel is dysregulated in the brain, less acetylcholine and dopamine is released. Cognitive confusion and uncoordinated motor function arises from this dysregulated system.
SAK3 binds directly to the subunit of this channel, enhancing neurotransmission and so improving cognitive deficits. The researchers found that the same process also seemed to work in a mouse model of Lewy body dementia, which is characterised by a buildup of proteins known as Lewy bodies.
“Even after the onset of cognitive impairment, SAK3 administration significantly prevented the progression of neurodegenerative behaviors in both motor dysfunction and cognition,” Prof Fukunaga said.
In comparison, Aduhelm, the Alzheimer’s drug recently approved by the US Food and Drug Administration, reduces the number of amyloid plaques in the brain, but whether the amyloid reduction actually prevents further cognitive or motor decline in patients is not yet known. According to Prof Fukunaga, SAK3 helps destroy amyloid plaque – at least in mice.
SAK3 also helps destroy misfolded alpha-synuclein, which normally helps regulate neurotransmitter transmission in the brain. The misfolded protein can aggregate, contributing to what researchers suspect may be an underlying cause of neurodegenerative symptoms. This aggregation can also cause loss of dopamine neurons, which are associated with learning and memory.
“We found that chronic administration of SAK3 significantly inhibited the accumulation of alpha-synuclein in the mice,” Prof Fukunaga said, noting that the mice received a daily oral dose of SAK3.
According to Prof 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 wreak havoc in 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.”
The team published their results in the International Journal of Molecular Sciences. This treatment candidate has been declared safe by Japan’s governing board, and the researchers are planning to start human clinical trials in the next year.
Source: Tohoku University
Journal information: Xu, J., et al. (2021) T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model. International Journal of Molecular Sciences. doi.org/10.3390/ijms22126185.
