A deficit in astroglial organization causes the impaired reactive sprouting in human apolipoprotein E4 targeted replacement mice.
The epsilon4 allele of apolipoprotein (apo)E associates with an increased risk of developing Alzheimer's disease (AD) as well as an earlier age of onset. However, the exact mechanisms by which apoE4 confers such susceptibility is currently unknown. We used a human apoE targeted replacement (hE-TR) mouse model to investigate the allele-specific response to entorhinal cortex lesion (ECL). We observed a marked impairment in reactive sprouting in hE4 mice compared to hE3 mice. ApoE expression was similar between genotypes at days post-lesion (DPL) 2 and 14. Thirty days post-lesion, hE4 mice had more reactive astrocytes as well as a defective outward migration pattern of the astrocytes in the dentate gyrus. The expression of the anti-inflammatory cytokine IL-1ra was delayed in hE4 mice compared to hE3 mice. ApoE and beta-amyloid (Abeta) 1-40 accumulated at 30 DPL in hE4 mice. These results suggest that the presence of apoE4 delays the astroglial repair process and indirectly compromises synaptic remodeling.
Blain
Jean-François
JF
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H4A 2B4.
Sullivan
Patrick M
PM
Poirier
Judes
J
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D020022:Genetic Predisposition to Disease; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053590:Interleukin 1 Receptor Antagonist Protein; D051379:Mice; D009416:Nerve Regeneration / Q000235:genetics*; D012795:Sialoglycoproteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins