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ApoE4 Accelerates Early Seeding of Amyloid Pathology.

Neuron | Dec 6, 2017

Accumulation and aggregation of amyloid-β (Aβ) in the brain is an initiating step in the pathogenesis of Alzheimer's disease (AD). The ε4 allele of apolipoprotein E (apoE) gene is the strongest genetic risk factor for late-onset AD. Although there is strong evidence showing that apoE4 enhances amyloid pathology, it is not clear what the critical stage(s) is during amyloid development in which apoE4 has the strongest impact. Using apoE inducible mouse models, we show that increased expression of astrocytic apoE4, but not apoE3, during the seeding stage of amyloid development enhanced amyloid deposition and neuritic dystrophy in amyloid model mice. ApoE4, but not apoE3, significantly increased brain Aβ half-life measured by in vivo microdialysis. Furthermore, apoE4 expression increased whereas apoE3 reduced amyloid-related gliosis in the mouse brains. Together, our results demonstrate that apoE4 has the greatest impact on amyloid during the seeding stage, likely by perturbing Aβ clearance and enhancing Aβ aggregation.

Pubmed ID: 29216449 RIS Download

Mesh terms: Alzheimer Disease | Amyloidosis | Animals | Apolipoprotein E3 | Apolipoprotein E4 | Astrocytes | Brain | Gene Knock-In Techniques | Gliosis | Humans | Mice | Mice, Transgenic | Neurites

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Associated grants

  • Agency: NIA NIH HHS, Id: R01 AG035355
  • Agency: NIA NIH HHS, Id: R01 AG046205
  • Agency: NIA NIH HHS, Id: P50 AG016574
  • Agency: NINDS NIH HHS, Id: P01 NS074969
  • Agency: NIA NIH HHS, Id: RF1 AG051504
  • Agency: NIA NIH HHS, Id: R01 AG027924
  • Agency: NIA NIH HHS, Id: R37 AG027924
  • Agency: NIA NIH HHS, Id: RF1 AG056130

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