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Targeting lysosomal acidification to restore microglial homeostasis and mitigate memory decline during male brain
Lorenzo Barrella1, María Pilar Ramírez-Ponce1, Victoria Vázquez-Román2
1Dpto. de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Spain.
Abstract:
Lysosomal dysfunction lies at the nexus of inflammaging, microglial dystrophy and synaptic fragility, making it an attractive target for brain rejuvenation. Here we demonstrate that a five-month oral course of ketotifen, an approved H1-antihistamine and mast-cell stabiliser, re-acidifies lysosomes in aged C57BL/6J male mice, restoring the quinacrine signal of peripheral macrophages and SIM-A9 microglia. This proton rebound is coupled to broad anti-cytokine effects: ketotifen attenuates lipopolysaccharide-evoked release of TNF-α, IL-1β and IL-10 in vitro and ex vivo. In the brain, the drug restores a highly ramified, homeostatic microglial morphology throughout the cortex and hippocampus. Ketotifen robustly elevates cortical synaptophysin and PSD-95 above age-matched levels. Behaviourally, ketotifen enhances spatial learning and object-location memory without altering locomotor activity or anxiety-like behaviour. Collectively, these findings identify lysosomal re-acidification as the initiating trigger of a multifaceted rejuvenation cascade that dampens multi-cytokine signalling, restores microglial morphology and preserves synaptic integrity. Because ketotifen is inexpensive, brain-permeable and already licensed for human use, our work unveils an immediately actionable geroprotective strategy to forestall early cognitive decline.
Insights
Ketotifen, an antihistamine, rejuvenates aged mouse brains by re-acidifying lysosomes. This drug improves microglial morphology, synaptic integrity, and cognitive function, offering a potential strategy against age-related cognitive decline.
Area of Science:
- Neuroscience
- Gerontology
- Pharmacology
Background:
- Lysosomal dysfunction is linked to brain aging, including inflammaging, microglial changes, and synaptic fragility.
- Targeting lysosomal function presents an opportunity for brain rejuvenation strategies.
Purpose of the Study:
- To investigate the effects of ketotifen, an H1-antihistamine and mast-cell stabilizer, on lysosomal function and brain aging in aged mice.
- To determine if ketotifen can reverse age-related deficits in microglial morphology, synaptic integrity, and cognitive function.
Main Methods:
- A five-month oral administration of ketotifen to aged C57BL/6J male mice.
- Assessment of lysosomal re-acidification using quinacrine fluorescence in macrophages and microglia.
- Measurement of cytokine levels (TNF-α, IL-1β, IL-10) in response to lipopolysaccharide.
- Evaluation of microglial morphology, synaptic markers (synaptophysin, PSD-95), and behavioral tests (spatial learning, object-location memory, locomotor activity, anxiety).
Main Results:
- Ketotifen re-acidified lysosomes in aged mice, restoring lysosomal function.
- The drug exhibited broad anti-cytokine effects, attenuating LPS-induced cytokine release.
- Ketotifen restored homeostatic microglial morphology and increased levels of synaptic proteins.
- Behavioral studies showed enhanced spatial learning and memory without affecting locomotion or anxiety.
Conclusions:
- Lysosomal re-acidification is a key mechanism for ketotifen-mediated brain rejuvenation.
- Ketotifen dampens neuroinflammation, restores microglial health, and preserves synaptic integrity in aged brains.
- Ketotifen represents a readily available, geroprotective strategy for mitigating age-related cognitive decline.
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