Amyloid beta governs mitochondrial lipid metabolism defects and neurodegenerative lysosomal stress.

In aged CerS1top/top mice, catalytically inactive CerS1 is linked to mitochondrial dysfunction, behavioral deficits, and amyloid-positive plaque accumulation.

• Why it matters: The study addresses how amyloid peptides connect to mitochondrial lipid metabolism defects and impaired mitophagy in Alzheimer’s disease, which remains unclear.
• What they did: It combined analyses of APP or Aβ40 versus Aβ42 proximity with TOM20/TOM40, CerS1/C18-ceramide and mitophagy readouts in neuronal, mouse, and human AD tissues, plus Pen-Cera-LCL768 in aged 3xTg and CerS1top/top mice.
• The result: Pen-Cera-LCL768 increased mitophagy-related readouts, reduced plaque burden, and improved behavior in aged 3xTg and CerS1top/top mice, while Mdivi-1 attenuated effects in 3xTg mice.

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