We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-beta peptides (Abeta) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Abeta, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe(-/-) astrocytes do not degrade Abeta present in Abeta plaque-bearing brain sections in vitro. Coincubation with antibodies to either Apoe or Abeta, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks Abeta degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe(-/-) astrocytes do not respond to or internalize Abeta deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited Abeta species by astrocytes, a process that may be impaired in Alzheimer disease.
Background and Purpose-Activation of transcription factor nuclear factor-B (NF-B) may induce expression of either proinflammatory/apoptotic genes or antiapoptotic genes. Because a considerable number of middle cerebral artery occlusions (MCAOs) in humans are not associated with reperfusion during the first 24 hours, the role of NF-B after permanent MCAO (pMCAO) was investigated. Methods-Mice transgenic for a NF-B-driven -globin reporter were exposed to pMCAO, and the expression of the reporter gene was quantified with real-time polymerase chain reaction. Mice lacking the p50 subunit of NF-B and wild-type controls were exposed to pMCAO with or without treatment with pyrrolidinedithiocarbamate (PDTC), an NF-B inhibitor. Brain sections of human stroke patients were immunostained for the activated NF-B. Results-pMCAO increased NF-B transcriptional activity to 260% (36.9Ϯ4.5 compared with 14.4Ϯ2.6; nϭ10; PϽ0.01) in the brain; this NF-B activation was completely blocked by PDTC (17.2Ϯ2.6; nϭ9; PϽ0.05). In p50 Ϫ/Ϫ mice, pMCAO resulted in 41% (18Ϯ3.2 mm 3 ; nϭ12) smaller infarcts compared with wild-type controls (32.9Ϯ3.8 mm 3 ; nϭ9; PϽ0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6Ϯ4.2 mm 3 ; nϭ8). Pro-DTC, a PDTC analogue that does not cross the blood-brain barrier, had no effect, even though Pro-DTC and PDTC were equally protective in vitro. During the first 2 days of human stroke, NF-B was activated in neurons in the penumbral areas.
Conclusions-NF-B is induced in neurons during
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