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Fig. 3 | Molecular Neurodegeneration

Fig. 3

From: APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

Fig. 3

Potential mechanisms underlying APOE2 protective effects against AD. CNS APOE is produced primarily by astrocytes, and also by activated microglia. Newly synthesized APOE is lipidated through cell surface ABCA1 or ABCG1, generating HDL-like lipoprotein particles. In the CNS, APOE2-containing lipoprotein particles are more lipidated than APOE3 and APOE4-containing particles, thus are larger in size. The lipidation of APOE can be modulated by targeting the transcription factors, LXR, and RXR, which regulate the expression of APOE and ABCA1. Lipidated APOE plays a critical role in lipid transport from astrocytes to neurons. Due to hyperlipidation, APOE2-containing lipoprotein particles likely deliver lipids to neurons at a higher efficiency than APOE3 and APOE4. APOE2 may also maintain synaptic plasticity during AD, potentially through interacting with synaptic APOE receptors. During AD pathogenesis, Aβ is produced primarily by neurons through proteolytic processing of APP. APOE regulates Aβ metabolism in an isoform-dependent manner. APOE2 likely mediates Aβ clearance via BBB at a higher efficiency than APOE3 and APOE4. In addition, APOE2 may have a stronger effect in promoting the proteolytic degradation of Aβ by extracellular enzymes. The regulatory roles of APOE in Aβ metabolism may be partially mediated through APOE/Aβ complex formation. APOE*ε2 has also been associated with reduced neurofibrillary tangles in AD patients, though the mechanism is unclear. Additionally, APOE2 may confer protection against AD by affecting the plasma lipid and metabolomics profiles. ACID, intracellular domain of the amyloid-precursor protein; sAPPβ, soluble amyloid precursor protein β

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