Apolipoprotein E deficiency increased microglial activation/CCR3 expression and hippocampal damage in kainic acid exposed mice.
Apolipoprotein E (apoE) down-regulates microglial activation and the secretion of inflammatory molecules in an isoform specific fashion (E2 > E3 > E4); the E4 isoform is over-represented in Alzheimer cases while E2 is under-represented. To better define the role of apoE in neurodegeneration, we contrasted apoE knockout (n = 38) and wild-type mice (n = 41) with respect to seizure activity, mortality, locomotion, hippocampal microglial activation/chemokine receptor expression, and damage to the hippocampus after nasal administration of kainic acid (KA) (water as controls). Mice lacking apoE demonstrated more hunching and less rearing, more damage to neurons in the CA3 region (mean histopathologic score: 3.7 vs. 1.6, p < 0.05), greater microglial activation confirmed by high levels of CD11b and CD86 expression in hippocampus (CD11b p < 0.01, CD86 p < 0.05), and a greater percentage of activated microglia expressing CC chemokine receptors 3 (CCR3) (p < 0.05). Taken together, these findings imply that apoE modulates hippocampal damage induced by KA and found early in the sequence of human Alzheimer's brain changes, by modulating microglial activation.
Duan
Rui-Sheng
RS
Division of Experimental Geriatrics (Novum, plan 5), Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
Chen
Zhiguo
Z
Dou
Ying-Chun
YC
Concha Quezada
Hernan
H
Nennesmo
Inger
I
Adem
Abdu
A
Winblad
Bengt
B
Zhu
Jie
J
D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D051940:B7-2 Antigen / Q000378:metabolism; D001522:Behavior, Animal; D039481:CD11b Antigen / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009460:Neurologic Examination / Q000379:methods; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000378:metabolism*
D001057:Apolipoproteins E; D051940:B7-2 Antigen; C515350:CCR3 protein, human; D039481:CD11b Antigen; C515351:Ccr3 protein, mouse; D018690:Excitatory Amino Acid Agonists; D000949:Histocompatibility Antigens Class II; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D007608:Kainic Acid