LIPID METABOLISM IN ASTROCYTES: GATEKEEPER OF POST-STROKE REPAIR

Ischemic stroke is a leading cause of death and disability in adults. After stroke, the brain undergoes acute damage, followed by repair processes, supported by metabolic rewiring. Astrocytes form a functional syncytium linking capillaries to neurons, enabling metabolic support of neuronal energy demands, and astrocytic lipid metabolism plays a key role in detoxification and myelination.
We hypothesize that post-stroke metabolic reprogramming, particularly in astrocytes, is critical for damage-repair transition, and functional recovery. To investigate this, we used an astrocyte-specific carnitine-palmitoyl-transferase-1A (CPT1A, the rate-limiting enzyme for long-chain fatty acids to enter mitochondria) knockout model subjected to cerebral ischemia (tMCAo).
No differences in infarct volume 24 hours after ischemia were observed between genotypes. On day 7, astrocytes in the damaged hemisphere show a comparable impairment in mitochondrial respiration, while by day 30, mitochondrial function recovers more efficiently in control astrocytes compared to CPT1A KO astrocytes. Consistently, CPT1A KO mice showed increased neuronal damage and gliosis on day 7, persistent on day 30. Targeted serum lipidomics revealed alterations in sphingolipids, suggesting impaired remyelination in CPT1A KO mice. Moreover, while no major differences are observed on day 7, WT mice display recovery of the axonal network and myelination by day 30, whereas CPT1A KO mice fail to show comparable improvement. These structural alterations correlated with persistent behavioural deficits, indicating that astrocytic lipid metabolism is essential for post-stroke repair and functional recovery.
Funded by ISCIII (PI24/00810, RD24/0009/0005; co-funded by the EU); EU’s Horizon Europe R&I program under the MSCA Doctoral Networks 2021 (101072759; ETERNITY).