Longevity Briefs: A Supplement That Could Restore Synaptic Plasticity In Alzheimer’s

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Decades of work have failed to make any significant progress in the treatment of Alzheimer’s disease, which is concerning given the fact that the global population is ageing. This means that the proportion of the population living with Alzheimer’s disease is increasing relative to the number of people available to care for them. The biggest risk factor for Alzheimer’s disease is not a genetic or lifestyle factor – it’s your age, and so targeting the fundamental biology of ageing is likely to be the best way to prevent Alzheimer’s, or at least slow its progression. But ageing is a complicated web of processes, and identifying which of these processes are fundamental drivers of Alzheimer’s is not easy.

One candidate is alpha‑ketoglutarate (AKG), a key component of the Krebs cycle – the series of chemical reactions necessary for aerobic respiration (the production of the ‘cellular fuel’ ATP in the mitochondria using oxygen). AKG is just one intermediate in the Krebs cycle, but it also has important roles outside of the mitochondria, such as in the regulation of gene expression and the recycling of damaged proteins. As we age, AKG is increasingly in demand for various reasons. Previous research has suggested that restoring AKG levels in mice can extend lifespan and improve health. In this study, researchers investigate whether AKG or a calcium-AKG salt (CaAKG) can restore synaptic plasticity in an Alzheimer’s mouse model. Plasticity represents the ability of synaptic connections to strengthen in response to repeated electrical impulses (long-term potentiation, LTP) or to weaken with disuse (long-term depression, LTD).

The discovery:

The researchers found that both AKG and CaAKG could “rescue” impaired synaptic plasticity in APP/PS1 mice. This is a widely used genetic mouse model of Alzheimer’s disease in which mice overproduce amyloid‑β (the misfolded protein that accumulates in Alzheimer’s disease), leading to memory problems.

The researchers first prepared slices of tissue from the hippocampus (a part of the brain that is particularly important for spatial memory). They then recorded field synaptic responses in a region of the hippocampus called CA1, which is essential for converting short term memory into long-term memory and is severely affected in Alzheimer’s disease. Field synaptic responses are measured by stimulating a group of neurons that is known to form downstream synaptic connections with the target (in this case CA1 neurons) and measuring how the target neurons respond. A weaker response suggests impaired synaptic transmission.

The researchers applied repeated stimulation to upstream neurons, either in the presence of control solution, AKG or CaAKG. Repeated stimulation should result in a strengthening of the synaptic connections (LTP) between the stimulated neurons and the CA1 neurons they project to. The researchers found that while some LTP occurred in hippocampal slices from Alzheimer’s mice, it was weak and short-lasting in comparison to slices from normal mice. In those slices treated with either CaAKG or pure AKG, however, LTP was much stronger and was maintained for at least 4 hours after the repeated stimulation.

Further research suggested that CaAKG and AKG worked in part by enhancing calcium entry into cells, as well as by enhancing autophagy (the cell’s’ waste disposal/recycling’ system). Autophagy allows cells to maintain the quality and function of the synaptic proteins that are essential for LTP to occur.

The implications:

This study offers encouraging preclinical evidence that AKG might be able to improve synaptic function in Alzheimer’s disease. AKG can be taken orally and is able to cross the blood‑brain barrier, making it an appealing candidate for human clinical trials, some of which are already underway. In Alzheimer’s disease, soluble amyloid beta binds to receptors that are essential for LTP and reduces their expression on the surface of the cell. AKG may indirectly combat this by providing alternative routes of calcium entry (which is necessary for LTP) and by enhancing autophagy, which helps with the clearance of amyloid beta and improves the quality of the proteins necessary for LTP. Interestingly, the researchers found that rapamycin (an immune system-modulating drug that also enhances autophagy and is under investigation for its effects on ageing) had similar effects on LTP to AKG.

We have to keep in mind that this study was conducted in tissue samples from mice genetically engineered to overproduce amyloid beta, which means that amyloid beta may be playing a bigger role in these animals than it does in the human version of the disease. It also doesn’t show that AKG actually improves cognitive performance, though other studies in living animals do suggest this (once again with the caveat that these animals have often been altered to develop an accelerated version of Alzheimer’s disease).

AKG is available as a dietary supplement, though currently there are no large-scale human trials showing improved cognitive performance, either in Alzheimer’s patients or healthy ageing individuals.