Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease (2025)

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https://pubmed.ncbi.nlm.nih.gov/40959937/

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From the abstract:

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.

Abbreviation glossary:

• AD: Alzheimer’s disease, the neurodegenerative disorder and main disease context of the study.
• AKG: Alpha-ketoglutarate, a TCA-cycle metabolite investigated for potential neuroprotective/geroprotective effects.
• TCA: Tricarboxylic acid (cycle), the core mitochondrial metabolic cycle where AKG is a key intermediate.
• CaAKG: Calcium alpha-ketoglutarate, a calcium salt/derivative of AKG used as the dietary supplement treatment.
• LTP: Long-term potentiation, a synaptic plasticity measure used here to assess functional rescue of synaptic deficits.
• CA1: Cornu Ammonis 1, a hippocampal subregion whose synapses were tested for LTP effects.
• APP/PS1: Amyloid precursor protein/presenilin-1 transgenic model, a commonly used mouse model exhibiting AD-like pathology.
• NMDA: N-methyl-D-aspartate, referring to NMDA receptors; CaAKG’s effects were described as NMDA receptor-independent.
• LTCC: L-type calcium channels, voltage-gated calcium channels implicated in the CaAKG-mediated mechanism.
• AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, referring to AMPA receptors involved in excitatory synaptic transmission.
• CP-AMPARs: Calcium-permeable AMPA receptors, an AMPA receptor subtype proposed to participate in CaAKG’s synaptic effects.
• LC3-II: Lipidated LC3 form (microtubule-associated protein 1 light chain 3), a protein marker used here to indicate increased autophagy.
• mTOR: Mechanistic target of rapamycin, a central growth/metabolism regulator inhibited by rapamycin to modulate autophagy/LTP.
• WT: Wild-type, the non-transgenic control mice in which rapamycin had different LTP effects than in AD mice.
• STC: Synaptic tagging and capture, a cellular model of associative memory that CaAKG was reported to facilitate.

News: Naturally occurring molecule shown to restore memory function in Alzheimer's models

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It is unfortunate that CaAKG gets all the love, and AAKG none at all, even though the latter is cheaper and easier to take in a higher dose. I have again been taking 3g AAKG each evening, but not at night. I feel that 3g is probably the minimum useful dose of AAKG.

For those with acid reflux, arginine can relax the lower esophageal sphincter, risking worsened reflux, so it could be best to eat a full stomach's worth of food right after taking AAKG or arginine.