Alzheimer's disease (AD) & Apolipoprotein E (APOE)

The study explores the initiation of Alzheimer's disease (AD) through the seeded growth of pathogenic protein aggregates. It highlights the genetic link of sporadic Alzheimer's disease (AD) to apolipoprotein E (APOE) and genes in microglia associated with immune, lipid, and endocytic functions. Researchers developed a transgenic mouse model expressing HaloTag-tagged APOE to purify APOE biochemically. They discovered fibrillary aggregates of APOE in mice with amyloid-beta (Ab) amyloidosis and human AD brains. These aggregates, which bind to beta sheet-binding dyes, trigger Ab amyloidosis in microglia's endo-lysosomal system, influenced by lipid metabolism and the JAK/STAT pathway. The study proposes that microglial uptake and aggregation of APOE may initiate Amyloid-beta (Aß, Abeta) / Amyloid Plaques formation in AD.
Kaji et al. 2024 Immunity 57: 2651-2668

In a healthy brain, Apolipoprotein E (APOE) is mostly made by astrocytes. Like other similar proteins, APOE helps dissolve fats in particles called lipoproteins
Ladu et al. 2000 Ann N.Y. Acad Sci 903: 167-175
Rebeck 2017 J Lipid Res 58: 1493-1499
Koutsodendris et al. 2022 Annu Rev Pathol 17: 73-99

These particles are then taken into cells through a process called receptor-mediated endocytosis. Once inside, the fats help with important cell functions like keeping cells alive, forming new connections, and extending cell membranes
Mauch et al. 2001 Science 294: 1354-1357
Saher 2005 Nat Neurosci 8: 468-475
Camargo et al. 2017 PLoS Biol 15: e1002605
Ioannou et al. 2019 Cell 177: 1522-1535
Blanchard et al. 2022 Nature 611: 769-779

Besides managing fats, APOE is also crucial in brain diseases.
Yamazaki et al. 2019 Nat Rev Neurol 15: 501-518
Chen et al. 2021 Neuron 109: 205-221
Serrano-Pozo et al. 2021 Lancet Neurol 20: 68-80

The Apolipoprotein E (APOE) gene is especially significant because its protein isoform known as Apolipoprotein E (APOE) 4 (APOE4) increases the risk of Alzheimer's disease (AD) the most
Jansen et al. 2019 Nat Genet 51: 404-413
Yamazaki et al. 2019 Nat Rev Neurol 15: 501-518
Chen et al. 2021 Neuron 109: 205-221
Wightman et al. 2021 Nat Genet 53: 1276-1282

Any injury to the CNS, like Alzheimer's disease (AD), makes microglia and astrocytes react. This reaction increases lipid metabolism, especially Apolipoprotein E (APOE). Age, sex, and genes are the major risk factors for Alzheimer’s disease, and they modulate the microglia response to Amyloid-beta (Aß, Abeta) / Amyloid Plaques.
Keren-Shaul et al. 2017 Cell 169: 1276-1290
Krasemann et al. 2017 Immunity 47: 566-581
Jansen et al. 2019 Nat Genet 51: 404-413
Sala Frigerio et al. 2019 Cell Rep 27: 1293-1306
Habibet al. 2020 Nat Neurosci 23: 701-706

In an Alzheimer's disease model, Apolipoprotein E (APOE) aids in the formation of neuritic and cerebrovascular plaques. Studies in mice show that losing Apolipoprotein E (APOE) reduces Amyloid-beta (Aß, Abeta) / Amyloid Plaques buildup. This suggests APOE helps in forming and stabilizing these plaques. The absence of apolipoprotein E significantly decreases the accumulation of amyloid beta-peptide.
Bales et al. 1997 Nat Genet 17: 263-264
Holtzman et al. 2000 Ann Neurol 47: 739-747
DeMattos et al. 2004 Neuron 41: 193-202

see also:
Alzheimer's disease (AD) & Immunity
Alzheimer's Disease (AD) & Pathogenicity
Apolipoprotein E (APOE)
Apolipoprotein E (APOE) 4 (APOE4)
Lipoproteins
Oligodendrocytes