Journal Club will be held on our Facebook Page on, February 6th at 13:00 EST/18:00 UK. This was due to be held on January 30th but due to a problem at Cooper Union University where the stream is broadcast and presented from we have had to change the date.
We will be discussing the new drug J147 which targets mitochondrial dysfunction to potentially treat Alzheimer’s and other age-related diseases. We have also discussed the topic in an article last week if you wish to read about the progress being made with this drug.
Aging is a major driving force underlying dementia, such as that caused by Alzheimer’s disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age-associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in several mouse models of AD. Here, we identify the mitochondrial α-F1-ATP synthase (ATP5A) as a target for J147. By targeting ATP synthase, J147 causes an increase in intracellular calcium leading to sustained calcium/calmodulin-dependent protein kinase kinase β (CAMKK2)-dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age-associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila. Our results link aging and age-associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two.
We will be live on Facebook from 13:00 EST/18:00 UK so come along and ask questions and join in with the discussion, this is an exciting study which has great potential for treating age-related diseases. We look forward to seeing you soon.
Goldberg, J., Currais, A., Prior, M., Fischer, W., Chiruta, C., Ratliff, E., … & Cuezva, J. M. (2018). The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging cell.