β-amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice.
β-amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice.
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DOI：
10.1186/alzrt262
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Wilcock DM
中科院分区：
文献类型：
--
作者：
Sudduth TL;Weekman EM;Brothers HM;Braun K;Wilcock DM
血管性痴呆是仅次于阿尔茨海默病(AD)的第二大常见原因。此外，据估计，几乎一半的AD患者有明显的脑血管疾病，并与他们的AD病理。我们假设脑血管疾病显著影响AD的病理进展。我们使用了一个脑血管疾病的饮食模型，该模型依赖于高同型半胱氨酸血症(HHcy)的诱导。HHcy是中风、心血管疾病和2型糖尿病的重要临床危险因素。在本研究中，我们在APP/PS1转基因小鼠中诱导了HHcy。在β-淀粉样蛋白(A-β)总负荷量不变的情况下，同型半胱氨酸APP/PS1小鼠实质中的嗜中性淀粉样蛋白沉积减少，血管中的淀粉样蛋白沉积显著增加，表现为脑淀粉样血管病变(CAA；血管淀粉样沉积)。我们还发现，与野生型小鼠相比，HHcy在APP/PS1小鼠中诱导了更多的微出血，并将神经炎性表型从M2a偏向状态转换为M1偏向状态。与这些变化相关的是基质金属蛋白酶2(MMP2)和MMP9系统的诱导。有趣的是，在HHcy 6个月后，APP/PS1小鼠的认知能力比野生型HHcy小鼠或APP/PS1小鼠更差，这表明脑血管病理和淀粉样蛋白沉积的相加效应。这些数据表明，脑血管疾病可以显著影响Aβ在大脑中的分布，有利于血管沉积。我们预测阿尔茨海默病合并脑血管疾病的存在将对阿尔茨海默病的进展和治疗效果产生重大影响。
Vascular dementia is the second most common cause of dementia after Alzheimer’s disease (AD). In addition, it is estimated that almost half of all AD patients have significant cerebrovascular disease comorbid with their AD pathology. We hypothesized that cerebrovascular disease significantly impacts AD pathological progression. We used a dietary model of cerebrovascular disease that relies on the induction of hyperhomocysteinemia (HHcy). HHcy is a significant clinical risk factor for stroke, cardiovascular disease and type 2 diabetes. In the present study, we induced HHcy in APP/PS1 transgenic mice. While total β-amyloid (Aβ) load is unchanged across groups, Congophilic amyloid deposition was decreased in the parenchyma and significantly increased in the vasculature as cerebral amyloid angiopathy (CAA; vascular amyloid deposition) in HHcy APP/PS1 mice. We also found that HHcy induced more microhemorrhages in the APP/PS1 mice than in the wild-type mice and that it switched the neuroinflammatory phenotype from an M2a biased state to an M1 biased state. Associated with these changes was an induction of the matrix metalloproteinase protein 2 (MMP2) and MMP9 systems. Interestingly, after 6 months of HHcy, the APP/PS1 mice were cognitively worse than wild-type HHcy mice or APP/PS1 mice, indicative of an additive effect of the cerebrovascular pathology and amyloid deposition. These data show that cerebrovascular disease can significantly impact Aβ distribution in the brain, favoring vascular deposition. We predict that the presence of cerebrovascular disease with AD will have a significant impact on AD progression and the efficacy of therapeutics.
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影响因子：
8.3
作者：
Candelario-Jalil E;Thompson J;Taheri S;Grossetete M;Adair JC;Edmonds E;Prestopnik J;Wills J;Rosenberg GA
通讯作者：
Rosenberg GA
影响因子：
--
作者：
Wilcock DM
通讯作者：
Wilcock DM
影响因子：
14.5
作者：
Reed, Bruce R.;Mungas, Dan M.;Chui, Helena C.
通讯作者：
Chui, Helena C.
影响因子：
82.9
作者：
Deane, R;Yan, SD;Zlokovic, B
通讯作者：
Zlokovic, B
影响因子：
4.4
作者：
Lee, JM;Yin, KJ;Xu, J
通讯作者：
Xu, J