Amyloid beta governs mitochondrial lipid metabolism defects and neurodegenerative lysosomal stress

Mechanisms linking amyloid peptides to mitochondrial dysfunction and impaired mitophagy in Alzheimer’s disease (AD) remain poorly defined. Here, we report that, in healthy aging neurons, mitochondrial ceramide synthase 1 (CerS1) localization accompanies increased mitochondrial C18-ceramide and mitophagy in damaged mitochondria. In neuronal, mouse, and human AD tissues, amyloid precursor protein (APP) or Aβ40, but not Aβ42, shows increased proximity or co-association with TOM20/TOM40 alongside reduced mitochondrial CerS1/C18-ceramide accumulation and mitophagy. Mitochondria-excluded mutant APP does not reproduce these responses in neuronal cells. WT-APP expression is associated with reduced p17/PERMIT–ICT1 proximity, which does not establish direct APP–ICT1 binding or disruption of complex formation. Reduced mitophagy also accompanies lysosomal Aβ42 accumulation and secretion from neurons. Aged CerS1top/top mice, expressing catalytically inactive CerS1, exhibit mitochondrial dysfunction, behavioral deficits, and amyloid-positive plaque accumulation. Treatment with the peptide-targeted nanoparticle Pen-Cera-LCL768, which accumulates in the brain after intranasal administration, increases mitophagy-related readouts, reduces plaque burden, and improves behavioral performance in aged 3xTg and CerS1top/top mice. Mdivi-1 attenuates treatment effects in 3xTg mice, but its lack of specificity limits conclusions about mitophagy dependence.