APOE genotype alters glial activation and loss of synaptic markers in mice.
The ε4 allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and affects clinical outcomes of chronic and acute brain damages. The mechanisms by which apoE affect diverse diseases and disorders may involve modulation of the glial response to various types of brain damage. We examined glial activation in a mouse model where each of the human APOE alleles are expressed under the endogenous mouse APOE promoter, as well as in APOE knock-out mice. APOE4 mice displayed increased glial activation in response to intracerebroventricular lipopolysaccharide (LPS) compared to APOE2 and APOE3 mice by several measures. There were higher levels of microglia/macrophage, astrocytes, and invading T-cells after LPS injection in APOE4 mice. APOE4 mice also displayed greater and more prolonged increases of cytokines (IL-1β, IL-6, TNF-α) than APOE2 and APOE3 mice. We found that APOE4 mice had greater synaptic protein loss after LPS injection, as measured by three markers: PSD-95, drebin, and synaptophysin. In all assays, APOE knock-out mice responded similar to APOE4 mice, suggesting that the apoE4 protein may lack anti-inflammatory characteristics of apoE2 and apoE3. Together, these findings demonstrate that APOE4 predisposes to inflammation, which could contribute to its association with Alzheimer's disease and other disorders.
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Yuangui
Y
Zhu
Evelyn
E
Nwabuisi-Heath
Sonya B
SB
Dumanis
Leon M
LM
Tai
Chunjiang
C
Yu
G William
GW
Rebeck
Mary Jo
MJ
LaDu
D000704:Analysis of Variance; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D053329:Apolipoprotein E2 / Q000235:genetics; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000172:deficiency; D001921:Brain / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
D000943:Antigens, Differentiation; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D016207:Cytokines; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C036763:monocyte-macrophage differentiation antigen; D051528:Guanylate Kinases