Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy
Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy
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DOI：
10.1073/pnas.1901659116
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发表时间：
2019-05-14
影响因子：
11.1
通讯作者：
Satoh-Asahara, Noriko
中科院分区：
文献类型：
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作者：
Inoue, Takayuki;Saito, Satoshi;Satoh-Asahara, Noriko
脑淀粉样血管病(CAA)是脑血管中淀粉样β蛋白沉积的结果。它经常伴随着阿尔茨海默病，并导致痴呆症。我们最近证明，在CAA的小鼠模型中，紫杉酯可以改善脑血流，促进脑内淀粉样β蛋白的清除，并预防口服时的认知功能障碍。在这里，我们发现紫杉林通过抑制ApoE-ERK1/2-淀粉样β蛋白前体蛋白轴抑制脑内淀粉样β蛋白的产生，尽管血脑屏障对紫杉林的通透性很低。髓样细胞2(TREM2)上触发受体的高表达水平与脑内炎症的加重有关。Taxiflin抑制炎症，减轻TREM2表达细胞在大脑中的积聚。它还减轻了谷氨酸水平和氧化组织损伤，并降低了大脑中活性半胱氨酸酶的水平，这表明细胞凋亡。因此，口服紫杉林通过抑制淀粉样β蛋白的产生和有益地调节促炎小胶质细胞的表型，对CAA具有多效性神经保护作用。
Cerebral amyloid angiopathy (CAA) results from amyloid-beta deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer's disease and causes dementia. We recently demonstrated that in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-beta removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-beta through suppressing the ApoE-ERK1/2-amyloid-beta precursor protein axis, despite the low permeability of the blood-brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-beta production and beneficially modulating proinflammatory microglial phenotypes.