Tier 4 — mechanistic

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

Navakkode S, Kennedy BK
Aging Cell 2025 Volume 24, issue 11, article e70235

Bibliography

PubMed
PMID 40959937
PubMed Central
PMC12610948
DOI
10.1111/acel.70235
Funding
The project was funded by the "NUHSRO/2020/114/Rethinking old drugs/BKK LOA"—Rethinking old drugs and natural products for aging and related diseases from NUS Medicine for B.K.K.
Competing interests
The authors declare no conflicts of interest.

Study snapshot

DesignInterventional ex vivo hippocampal slice electrophysiology with pharmacological co-treatment and Western blot analysis
ModelAPP/PS1 transgenic mice (APPSwe/PS1dE9) aged 4–5 months and age-matched C57BL/6 wild-type controls; acute hippocampal slices, CA1 region
Sample200 hippocampal slices from 51 APP/PS1 and 52 wild-type mice; both sexes
Intervention1 mM CaAKG or 1 mM AKG bath-applied to slices for 60 min around LTP induction; co-treatments with AP-5 (50 μM, NMDAR blocker), nifedipine (10 μM, L-type calcium channel blocker), IEM-1460 (30 μM, CP-AMPAR inhibitor), or rapamycin (1 μM, mTOR inhibitor)
DurationAcute: 60 min bath application (30 min before and after tetanus); 4-hour fEPSP recording per experiment
EndpointsLate-LTP magnitude (fEPSP slope, 4 h); Synaptic tagging and capture (STC) via strong-before-weak paradigm; LC3-II protein expression (autophagy marker, Western blot)

What the study showed, in plain terms

Alzheimer's disease damages the electrical connections between brain cells long before memory loss becomes obvious. This study asked whether calcium alpha-ketoglutarate (CaAKG) — a metabolite already shown to extend lifespan in mice — could restore those damaged connections in an Alzheimer's mouse model.

The researchers took hippocampal slices from APP/PS1 mice, which carry human genes that cause early-onset familial Alzheimer's disease, and measured a form of learning-related electrical activity called long-term potentiation. Untreated Alzheimer's slices failed to maintain this signal. Bathing the slices in CaAKG restored it to normal levels, and the rescue was stronger in female mice than in male mice — mirroring earlier lifespan findings.

The mechanism did not depend on NMDA receptors, the usual gateway for learning-related calcium entry. Instead, CaAKG worked through L-type calcium channels and calcium-permeable AMPA receptors, and it increased levels of LC3-II, a marker of autophagy — the cell's clearance system for damaged proteins. Rapamycin, a drug that also boosts autophagy, produced similar rescue. This ex vivo work suggests CaAKG may act through an autophagy-related pathway to preserve synaptic function in the Alzheimer's brain.

Key findings

  • 1 mM CaAKG or free AKG rescued long-term potentiation at hippocampal CA1 synapses of APP/PS1 mice for the full 4-hour recording, with a stronger effect in females than males (5-min fEPSP: 189% vs 155%, p = 0.0019).
  • The rescue was NMDA receptor-independent — co-application of the NMDAR blocker AP-5 did not prevent CaAKG-induced LTP in APP/PS1 slices.
  • The rescue was L-type calcium channel-dependent — co-application of nifedipine blocked CaAKG's effect in APP/PS1 mice but not wild-type mice.
  • The rescue also required calcium-permeable AMPA receptors — the CP-AMPAR inhibitor IEM-1460 abolished CaAKG-mediated LTP rescue in APP/PS1 mice.
  • CaAKG treatment significantly increased LC3-II expression in APP/PS1 hippocampal slices (p = 0.0152) but not in wild-type slices, indicating selective enhancement of autophagy in the disease context.
  • Rapamycin (1 μM, mTOR inhibitor) also rescued LTP in APP/PS1 mice while blocking LTP in wild-type mice, consistent with a shared autophagy-mediated mechanism.
  • CaAKG restored synaptic tagging and capture in APP/PS1 slices, converting a normally short-lasting early-LTP into a persistent late-LTP — a cellular correlate of associative memory formation.

What this study can and cannot tell us

This is an ex vivo hippocampal slice study, not a behavioural or systemic investigation. The authors did not measure whether CaAKG oral supplementation reaches the brain in APP/PS1 mice at concentrations sufficient to reproduce the 1 mM bath effects observed here, nor did they test cognitive performance in living animals.

The bath-applied 1 mM concentration is substantially higher than physiological plasma AKG in supplemented mice, and the pharmacokinetic gap between ex vivo application and oral dosing has not been closed.

The APP/PS1 model captures amyloid pathology and early synaptic dysfunction but does not fully replicate the tauopathy, neuroinflammation, and vascular components of human Alzheimer's disease. No human data on CaAKG in Alzheimer's or cognitive decline exist as of publication.

The stronger female rescue is intriguing but the mechanism — proposed to involve estrogen and inflammation — was not directly tested.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology