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Swedish–Danish preprint: Single-dose rapamycin increases brain glucose metabolism but reduces synaptic density in Long-Evans rats: A PET imaging study 2025

Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR), has shown promise as a neuroprotective compound in preclinical studies. Reduced brain glucose metabolism and loss of synaptic density are key features of Alzheimer’s disease that can be measured in vivo using positron emission tomography (PET) imaging, allowing for assessment of treatment effects on brain function. Here, we used PET to investigate the acute effects of a single-dose of rapamycin on glucose metabolism and synaptic density in Long-Evans rats. In a repeated measures design, we quantified changes in brain glucose metabolism using [18F]FDG PET (n=13) at baseline, one day, and one week after intraperitoneal administration of rapamycin (8 mg/kg). In a separate cohort (n=6), we measured synaptic density using [18F]SynVesT-1 PET at baseline and one day after rapamycin administration. Regional standardized uptake values (SUV) were calculated for [18F]FDG while total distribution volumes were estimated for [18F]SynVesT-1 using image-derived input functions of the heart. Rapamycin induced significant increases in [18F]FDG SUV across multiple brain regions one day after administration, an effect that persisted at one-week follow-up. In contrast, [18F]SynVesT-1 binding showed significant decreases throughout the brain at 24 hours post-administration, indicating reduced synaptic density. These opposing effects on glucose metabolism and synaptic density point to multifaceted actions of rapamycin in the brain, possibly reflecting improved metabolic function occurring simultaneously with acute synaptic loss. These results show that [18F]FDG and synaptic density PET imaging could serve as useful biomarkers in human clinical trials evaluating rapamycin’s mechanistic and therapeutic effects in neurodegenerative disorders.

The opposite changes we observed in metabolism and synaptic density indicate that rapamycin has divergent effects on brain processes. While our study design using separate cohorts for [18F]FDG and [18F]SynVesT-1 imaging precludes direct correlation between these measures, the findings point to potentially independent effects on energy metabolism and synaptic function. The increase in glucose metabolism may reflect enhanced cellular energy efficiency through mTOR inhibition, consistent with a previous study showing improved mitochondrial function and glycolysis following rapamycin treatment in AD mouse models [24]. The decrease in synaptic density could reflect an acute response to mTOR inhibition, as this pathway plays a key role in forming and regulating synaptic plasticity and protein synthesis [25,26]. These changes align with rapamycin’s established role in promoting autophagy and cellular stress resistance [27], processes that may temporarily reduce synaptic density while enhancing metabolic function.
Previous studies have demonstrated that mTOR signalling is essential for activity-dependent synapse formation in young neurons [28]. Importantly, the synaptic response to rapamycin appears to be age-dependent - while mTOR inhibition may suppress synaptogenesis and plasticity in young subjects, it could potentially have protective effects in aging brains where dysregulated mTOR signaling contributes to synaptic dysfunction and loss [29–31]. These differential age-dependent effects should be considered when interpreting our findings and evaluating the translational therapeutic potential of rapamycin in aged populations. However, we cannot exclude the possibility that rapamycin has detrimental effects on synaptic function, regardless of age. Further longitudinal in vivo imaging studies in older animals are therefore warranted.
Several limitations of our study should be considered when interpreting the findings. Importantly, both the [18F]FDG and [18F]SynVesT-1 experiments used a single-arm design without a placebo control group. While all animals received saline I.P. injections prior to scans where no rapamycin was administered, it cannot be excluded that the observed effects are caused to other factors than the drug itself, such as repeated anaesthesia

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#2

So the old mice in the ITP lived longer but with more feeble brains due to lower synaptic density😁?

They say the enhanced glucose metabolism persisted (week), whereas the lowering of synaptic density was “transient”. But that was with a single dose. What happens when the dose is weekly? And what happens when it is daily as with so many animal/mice studies? Perhaps with daily the “transient” becomes persistent, so for humans is weekly dosage safer?

Also, are these effects dose dependent? And did the delivery matter (mice in the ITP had oral delivery in food).

Interesting, but more questions than answers. More rapamycin studies focused specifically on the brain in humans would be nice. And the issue of BBB crossing is still not completely clear.

Very depressing - 2011, so almost 15 years ago :cry::

Fighting neurodegeneration with rapamycin: mechanistic insights

https://www.nature.com/articles/nrn3068

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