Summary: Increasing SIRT3 levels with a ketone rich diet may help protect GABAergic interneurons and delay the onset of Alzheimer’s disease.
A ketone-supplemented diet may protect neurons from death during the progression of Alzheimer’s disease, according to research in mice recently published in Journal of Neuroscience.
Early in the development of Alzheimer’s disease, the brain becomes over excited, potentially through the loss of inhibitory, or GABAergic, interneurons that keep other neurons from signaling too much. Because interneurons require more energy compared to other neurons, they may be more susceptible to dying when they encounter the Alzheimer’s disease protein amyloid beta. Amyloid beta has been shown to damage mitochondria – the metabolic engine for cells – by interfering with SIRT3, a protein that preserves mitochondrial functions and protects neurons.
Cheng et al. genetically reduced levels of SIRT3 in mouse models of Alzheimer’s disease. Mice with low levels of SIRT3 experienced a much higher mortality rate, more violent seizures, and increased interneuron death compared to the mice from the standard Alzheimer’s disease model and control mice. However, the mice with reduced levels of SIRT3 experienced fewer seizures and were less likely to die when they ate a diet rich in ketones, a specific type of fatty acid. The diet also increased levels of SIRT3 in the mice.
Increasing SIRT3 levels via ketone consumption may be a way to protect interneurons and delay the progression of Alzheimer’s disease.
Calli McMurray – SfN
The image is credited to Cheng et al., JNeurosci 2019.
Original Research: Closed access
“SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer’s Disease Model”. Aiwu Cheng, Jing Wang, Nathaniel Ghena, Qijin Zhao, Isabella Perone, M. Todd King, Richard L. Veech, Myriam Gorospe, Ruiqian Wan and Mark P. Mattson.
Journal of Neuroscience doi:10.1523/JNEUROSCI.1446-19.2019.
SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer’s Disease Model
Impaired mitochondrial function and aberrant neuronal network activity are believed to be early events in the pathogenesis of Alzheimer’s disease (AD), but how mitochondrial alterations contribute to aberrant activity in neuronal circuits is unknown. In this study, we examined the function of mitochondrial protein deacetylase sirtuin 3 (SIRT3) in the pathogenesis of AD. Compared to AppPs1 mice, Sirt3-haploinsufficient AppPs1 mice (Sirt3+/-AppPs1) exhibit early epileptiform EEG activity and Seizure. Both male and female Sirt3+/-AppPs1 mice were observed to die prematurely before five months of age. When comparing male mice among different genotypes, Sirt3 haploinsufficiency renders GABAergic interneurons in the cerebral cortex vulnerable to degeneration and associated neuronal network hyperexcitability. Feeding Sirt3+/-AppPs1 AD mice with a ketone ester-rich diet increases SIRT3 expression and prevents seizure-related death and the degeneration of GABAergic neurons, indicating that the aggravated GABAergic neuron loss and neuronal network hyperexcitability in Sirt3+/-AppPs1 mice are caused by SIRT3 reduction and can be rescued by increase of SIRT3 expression. Consistent with a protective role in AD, SIRT3 levels are reduced in association with cerebral cortical Aβ pathology in AD patients. In summary, SIRT3 preserves GABAergic interneurons and protects cerebral circuits against hyperexcitability, and this neuroprotective mechanism can be bolstered by dietary ketone esters.
GABAergic neurons provide the main inhibitory control of neuronal activity in the brain. By preserving mitochondrial function, SIRT3 protects parvalbumin and calretinin interneurons against Aβ-associated dysfunction and degeneration in AppPs1 AD mice, thus restraining neuronal network hyperactivity. The neuronal network dysfunction that occurs in AD can be partially reversed by physiological, dietary, and pharmacological interventions to increase SIRT3 expression and enhance the functionality of GABAergic interneurons.