Increased Spontaneous Central Bleeding and Cognition Impairment in APP/PS1 Mice with Poorly Controlled Diabetes Mellitus.
Increased Spontaneous Central Bleeding and Cognition Impairment in APP/PS1 Mice with Poorly Controlled Diabetes Mellitus.
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糖尿病控制不善的APP/PS1小鼠中自发性中心出血和认知障碍增加。
DOI：
10.1007/s12035-015-9311-2
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发表时间：
2016-05
影响因子：
5.1
通讯作者：
Garcia-Alloza M
中科院分区：
文献类型：
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作者：
Ramos-Rodriguez JJ;Infante-Garcia C;Galindo-Gonzalez L;Garcia-Molina Y;Lechuga-Sancho A;Garcia-Alloza M
阿尔茨海默病 (AD) 和血管性痴呆 (VaD) 是痴呆症最常见的病因，在许多情况下，两者的界限是模糊的。衰老仍然是患痴呆症的主要危险因素；然而，流行病学研究表明，糖尿病也可能导致AD。为了进一步研究这种关系，我们诱导了 APPswe/PS1dE9 (APP/PS1) 小鼠（AD 的经典模型）低胰岛素糖尿病。 APP/PS1 小鼠在 18 周龄时腹腔注射链脲佐菌素 (STZ)，此时 AD 病理学尚未在该动物模型中建立。在莫里斯水迷宫和新的物体辨别测试中评估 26 周龄时的认知能力。我们观察到 APP/PS1 小鼠中 STZ 诱导的情景记忆和工作记忆障碍显着恶化。尸检评估包括脑萎缩、β-淀粉样蛋白和 tau 蛋白病理、自发性出血和中枢炎症增加。有趣的是，在 APP/PS1-STZ 糖尿病小鼠中，我们检测到 Aβ 可溶性/不溶性水平向毒性更强的可溶性物质转变。 APP/PS1-STZ 小鼠的磷酸化 tau 水平也增加，并伴随着炎症过程的加剧，无论是在靠近老年斑 (SP) 的区域还是在无 SP 的区域。 APP/PS1-STZ 小鼠中出血的发生率明显更高，尽管周细胞和内皮仅部分受到影响，但血脑屏障的改变仍然可能是观察到的病理特征的基础。我们的数据支持糖尿病过程在 AD 和 VaD 中的含义，并且改善代谢控制可以延迟观察到的中枢病理学是可行的。
Alzheimer’s disease (AD) and vascular dementia (VaD) are the most common causes of dementia, and borderlines are blurred in many cases. Aging remains the main risk factor to suffer dementia; however, epidemiological studies reveal that diabetes may also predispose to suffer AD. In order to further study this relationship, we have induced hypoinsulinemic diabetes to APPswe/PS1dE9 (APP/PS1) mice, a classical model of AD. APP/PS1 mice received streptozotocin (STZ) ip at 18 weeks of age, when AD pathology is not yet established in this animal model. Cognition was evaluated at 26 weeks of age in the Morris water maze and the new object discrimination tests. We observed that STZ-induced episodic and working memory impairment was significantly worsened in APP/PS1 mice. Postmortem assessment included brain atrophy, amyloid-beta and tau pathology, spontaneous bleeding, and increased central inflammation. Interestingly, in APP/PS1-STZ diabetic mice, we detected a shift in Aβ soluble/insoluble levels, towards more toxic soluble species. Phospho-tau levels were also increased in APP/PS1-STZ mice, accompanied by an exacerbated inflammatory process, both in the close proximity to senile plaque (SP) and in SP-free areas. The presence of hemorrhages was significantly higher in APP/PS1-STZ mice, and although pericytes and endothelium were only partially affected, it remains possible that blood-brain barrier alterations underlie observed pathological features. Our data support the implication of the diabetic process in AD and VaD, and it is feasible that improving metabolic control could delay observed central pathology.