Reversing Alzheimer's: How a Metabolic Molecule Could Protect Memory

This study showed that a single molecule, called calcium alpha-ketoglutarate (CaAKG), improves communication between neurons in an animal model of Alzheimer's disease. Through experiments with mice, researchers demonstrated that this molecule restores mechanisms linked to memory, increases cellular cleaning, and strengthens brain connections, indicating its potential as a therapeutic strategy for Alzheimer's and brain aging.

Alpha-ketoglutarate (AKG) is a substance naturally produced by the body and essential for energy generation in cells. It is part of a set of reactions called the tricarboxylic acid cycle, which occurs within the mitochondria, the "power plants" of cells. Previous research has shown that AKG can increase longevity and improve health in various organisms, from microorganisms to mice.

These effects have sparked scientific interest in its possible role in protecting the brain during aging and in neurodegenerative diseases, such as Alzheimer's disease.

Several studies show that alterations in energy metabolism are associated with the progression of Alzheimer's disease. In particular, the activity of an enzyme called alpha-ketoglutarate dehydrogenase, responsible for an important step in cellular energy production, is reduced in brains affected by the disease.

This enzyme is especially abundant in brain regions linked to memory and learning, which are precisely the most affected in Alzheimer's disease. When its function is compromised by oxidative stress or toxins, communication between neurons is impaired, contributing to memory loss.

To overcome some limitations of common AKG, researchers used a modified form of the molecule called calcium alpha-ketoglutarate (CaAKG). This version is more stable, absorbed more slowly by the body, and remains active in the blood for longer.

Furthermore, because it is associated with calcium, it has better bioavailability, which facilitates its action in tissues, including the brain. Previous studies by the same group had already demonstrated that supplementation with CaAKG increases life expectancy and improves overall health in mice.

In this work, the researchers investigated whether AKG and CaAKG could improve communication between neurons in an animal model of Alzheimer's disease. For this, genetically modified mice (APP/PS1) were used, which develop brain alterations similar to those observed in patients with Alzheimer's disease.

Typical electrophysiology setup used to study electrical signals related to memory over long periods of time. Credit: NUS Medicine

Scientists analyzed slices of the hippocampus from these animals, a region fundamental to memory formation, and compared the results with healthy mice.

One of the main experiments evaluated so-called long-term potentiation, a phenomenon that represents the strengthening of connections between neurons after repeated stimulation. This process is considered one of the main cellular mechanisms of learning and memory. In mice with Alzheimer's, long-term potentiation was significantly reduced.

However, after treatment with AKG or CaAKG, researchers observed a marked improvement in this synaptic strengthening, especially in females, indicating a more pronounced protective effect in this group.

To understand how CaAKG produced these effects, the researchers analyzed the cellular mechanisms involved. Surprisingly, the effects did not depend on a type of receptor usually associated with memory, the NMDA receptor.

Instead, CaAKG acted through other pathways, including L-type calcium channels and AMPA receptors that allow calcium to enter neurons. These alternative systems help maintain synaptic communication even when traditional mechanisms are compromised by the disease.

Dr. Sheeja Navakkode and Prof. Brian Kennedy, in the laboratory of the Translational Research Program in Healthy Longevity. Credit: NUS Medicine

Furthermore, the scientists investigated whether CaAKG influenced autophagy, a natural “cellular cleaning” process that removes damaged components and helps maintain healthy neurons.

Through biochemical analyses, such as Western blot, an increase in markers associated with autophagy was observed in the brains of Alzheimer's mice treated with CaAKG. Similar results were observed with rapamycin, a substance known to stimulate autophagy, suggesting that this process may be one of the factors responsible for the improvement in synaptic function.

Another set of experiments evaluated the so-called synaptic labeling and capture, a mechanism related to associative memory, that is, the ability to link different pieces of information in the same memory. This process is impaired in Alzheimer's, even in the early stages of the disease.

Treatment with CaAKG restored this mechanism in mice with Alzheimer's, indicating that the compound not only improves individual connections but also helps the brain integrate information more efficiently.

Taken together, the results show that CaAKG can protect the brain against synaptic deficits associated with Alzheimer's disease through multiple mechanisms, including modulation of neuronal calcium and increased autophagy.

These findings suggest that strategies based on compounds that regulate metabolism and cellular health may represent a promising approach to slowing cognitive decline in aging and neurodegenerative diseases.

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Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer’s Disease

Sheeja Navakkode and Brian K. Kennedy

Aging Cell. 17 September 2025DOI: 10.1111/acel.70235

Abstract:

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function. Increasing evidence indicates that alpha-ketoglutarate (AKG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan and healthspan across various animal models, raising interest in its potential neuroprotective effects in age-related disorders such as AD. Our previous research found that dietary supplementation with calcium alpha-ketoglutarate (CaAKG), a calcium derivative of AKG, enhances both lifespan and healthspan in mice. However, little is known about the neuroprotective role of AKG/CaAKG in AD. Here, we show that CaAKG could rescue synaptic deficits that are associated with AD. Treatment with AKG or CaAKG ameliorates long-term potentiation (LTP) at hippocampal CA1 synapses in APP/PS1 mice, with a more profound effect in female AD mice than in males. The effects of CaAKG were mediated through an NMDA receptor-independent mechanism involving L-type calcium channels (LTCC) and calcium-permeable AMPA receptors (CP-AMPARs). Analysis of protein expression showed that AD hippocampal slices treated with CaAKG exhibited increased LC3-II levels, indicating enhanced autophagy. Similarly, rapamycin, an mTOR inhibitor, also rescued LTP deficits in AD mice, suggesting that the observed increase in autophagy may contribute to neuroprotection. Interestingly, rapamycin showed differential effects, as it rescued LTP in AD mice but blocked LTP in WT mice. We also observed that CaAKG facilitated synaptic tagging and capture (STC), a widely studied cellular model for associative memory, indicating its potential to facilitate associative memory. Overall, our findings suggest that CaAKG has neuroprotective effects in APP/PS1 mice. We propose CaAKG as a promising therapeutic target not only for aging but also for AD and potentially other age-associated neurodegenerative diseases, highlighting geroprotective strategies as viable alternatives for the prevention and treatment of AD.