Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer's disease.
Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer's disease.
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DOI：
10.1371/journal.pone.0023789
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Jefferies WA
中科院分区：
文献类型：
--
作者：
Biron KE;Dickstein DL;Gopaul R;Jefferies WA
在其他阿尔茨海默病（AD）病理学之前血脑屏障（BBB）完整性降低的证据提供了脑血管病和AD之间的强有力联系。然而，“血管假说”认为AD中的BBB渗漏可能是由于缺氧和神经炎症导致血管恶化和细胞凋亡。我们提出了一个替代假设：淀粉样蛋白生成促进广泛的新血管生成，导致血管通透性增加，随后在AD血管过度。脑血管完整性的特点是在Tg 2576 AD模型小鼠过表达的人淀粉样前体蛋白（APP）含有双错义突变，APPsw，发现在瑞典家庭，导致早发性AD。紧密连接（TJ）蛋白，occludin和ZO-1的表达，与细胞凋亡和血管生成的标志物一起进行了检查。在老年Tg 2576 AD小鼠中，与年龄匹配的野生型同窝小鼠和两种基因型的年轻小鼠相比，TJ破坏的发生率显着增加，与微血管密度增加直接相关，但与细胞凋亡无关，这强烈支持淀粉样蛋白引发的血管过多作为BBB破坏的基础。人类患者的血管过多在AD和对照的死后脑组织的比较中得到证实。我们的研究结果表明，淀粉样变性介导血脑屏障破坏和泄漏，通过促进新血管生成和血管增生，导致重新分配的TJ，维持屏障，从而提供了一个新的范例整合血管重塑与AD中观察到的病理生理学。因此，在AD脑中鉴定的广泛的血管生成表现出与在其他疾病（例如年龄相关性黄斑变性）的病理生理学中明显的新血管形成相似。
Evidence of reduced blood-brain barrier (BBB) integrity preceding other Alzheimer's disease (AD) pathology provides a strong link between cerebrovascular angiopathy and AD. However, the “Vascular hypothesis”, holds that BBB leakiness in AD is likely due to hypoxia and neuroinflammation leading to vascular deterioration and apoptosis. We propose an alternative hypothesis: amyloidogenesis promotes extensive neoangiogenesis leading to increased vascular permeability and subsequent hypervascularization in AD. Cerebrovascular integrity was characterized in Tg2576 AD model mice that overexpress the human amyloid precursor protein (APP) containing the double missense mutations, APPsw, found in a Swedish family, that causes early-onset AD. The expression of tight junction (TJ) proteins, occludin and ZO-1, were examined in conjunction with markers of apoptosis and angiogenesis. In aged Tg2576 AD mice, a significant increase in the incidence of disrupted TJs, compared to age matched wild-type littermates and young mice of both genotypes, was directly linked to an increased microvascular density but not apoptosis, which strongly supports amyloidogenic triggered hypervascularity as the basis for BBB disruption. Hypervascularity in human patients was corroborated in a comparison of postmortem brain tissues from AD and controls. Our results demonstrate that amylodogenesis mediates BBB disruption and leakiness through promoting neoangiogenesis and hypervascularity, resulting in the redistribution of TJs that maintain the barrier and thus, provides a new paradigm for integrating vascular remodeling with the pathophysiology observed in AD. Thus the extensive angiogenesis identified in AD brain, exhibits parallels to the neovascularity evident in the pathophysiology of other diseases such as age-related macular degeneration.
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影响因子：
64.5
作者：
Duce JA;Tsatsanis A;Cater MA;James SA;Robb E;Wikhe K;Leong SL;Perez K;Johanssen T;Greenough MA;Cho HH;Galatis D;Moir RD;Masters CL;McLean C;Tanzi RE;Cappai R;Barnham KJ;Ciccotosto GD;Rogers JT;Bush AI
通讯作者：
Bush AI
影响因子：
--
作者：
Dickstein, Dara L.;Walsh, Jessica;Brautigam, Hannah;Stockton, Steven D., Jr.;Gandy, Samuel;Hof, Patrick R.
通讯作者：
Hof, Patrick R.
影响因子：
4.8
作者：
Fossati, S.;Cam, J.;Rostagno, A.
通讯作者：
Rostagno, A.
影响因子：
2.1
作者：
Hardy, John
通讯作者：
Hardy, John
影响因子：
6
作者：
FERREIRO, JA;ANSBACHER, LE;VINTERS, HV
通讯作者：
VINTERS, HV