Aberrant protein S-nitrosylation in Alzheimer’s disease inhibits the TCA cycle, causing synaptic loss due to compromised mitochondrial metabolism. Treatment with dimethyl succinate bypasses this block, partially restoring mitochondrial function and reversing synapse loss, suggesting potential therapeutic strategies for addressing synaptic loss through mitochondrial energy metabolism rescue.
January 2024 – Advanced Science
- Aberrant protein s-nitrosylation and TCA cycle disruption: In Alzheimer’s disease, an abnormal modification of proteins through S-nitrosylation impairs the tricarboxylic acid (TCA) cycle, a critical pathway for cellular energy production. This disruption leads to decreased energy metabolism within neurons, contributing to their dysfunction and the progression of neurodegenerative conditions
- Mitochondrial metabolism’s role in synaptic health: The study highlights the crucial role of mitochondrial metabolism in maintaining synaptic health. Synapses, the points of communication between neurons, are highly dependent on the energy produced by mitochondria. When mitochondrial function is compromised, as seen in Alzheimer’s disease, synaptic loss occurs, leading to cognitive decline
- Reversing synaptic loss with dimethyl succinate: The research discovered that treating neurons with dimethyl succinate, a substance that can bypass the metabolic block in the TCA cycle, partially restores mitochondrial function. This recovery of mitochondrial activity leads to a reversal of synaptic loss, offering hope for interventions that could mitigate the effects of ageing on the brain
These findings open new avenues for developing therapeutic strategies aimed at preserving cognitive function in the elderly. By focusing on enhancing mitochondrial energy metabolism, it may be possible to slow or reverse aspects of cognitive decline associated with ageing, thereby improving quality of life and extending healthspan.
Read the article at: Andreyev, Alexander Y., et al. “Metabolic Bypass Rescues Aberrant S-nitrosylation-Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer’s Disease Human Neurons.” Advanced Science, 2024, doi:10.1002/advs.202306469.