Fig. 10

Vicious cycles in AD pathogenesis involving Aβ and NFT formation as well as disturbances in peroxisomal and mitochondrial metabolic pathways. In neurons (pink box), peroxisomal dysfunction includes reductions in catalase import, peroxisomal β-oxidation, and DHA and plasmalogen synthesis. This caused oxidative stress, accumulation of LCFAs/VLCFAs (exerting lipotoxicity) and changes in plasma membrane fluidity (exerting reduced synaptic plasticity) accompanied by an initial increase and a later fall in peroxisome numerical abundance. The resulting oxidative stress in turn elevates Aβ production, its aggregation and the formation of NFTs promoting the further disturbance in peroxisomal and mitochondrial dysfunction. Microglial cells (yellow box) are activated by Aβ and release TNFα, which also impairs catalase import, β-oxidation and DHA synthesis resulting in an imbalance of pro- and anti-inflammatory molecules thereby maintaining brain inflammation. TNFα-induced disturbance of peroxisomal function in oligodendrocytes (green box) affects myelin composition finally leading to demyelination, axon loss and a reduced synaptic transmission. The described vicious cycles are depicted in gray dotted lines with arrows indicating the rotation direction. Bold red arrows exemplify alterations (increases ↑ and decreases ↓); blue arrows represent the sequences of different processes with indications of reference numbers of corresponding publications in square brackets. Figure is created with BioRender.com