阿尔茨海默氏症患者大脑血流减少的罪魁祸首

你知道，在长时间躺下后，你站起来有点太快会感到头晕目眩吗？

这种感觉是由大脑血流量突然减少引起的，减少了约30％。现在想象一下每天每分钟生活的血流量都会减少。

患有阿尔茨海默病的人不必想象它。阿尔茨海默病患者脑血流减少的存在已有数十年的历史，但与认知功能受损的确切相关性却鲜为人知。

康奈尔大学生物医学工程副教授Chris Schaffer说：“人们可能会适应血流减少，因此他们不会一直感到头晕，但有明显的证据表明它会影响认知功能。”

来自Schaffer联合实验室和Nizimura西村副教授的一项新研究为这种急剧减少的血流提供了解释：白细胞粘附在毛细血管内部，是大脑中最小的血管。虽然只有一小部分毛细血管经历了这种阻塞，但每个停滞的血管导致多个下游血管中的血流减少，从而放大了对整个脑血流的影响。

他们的论文“脑毛细血管中的中性粒细胞粘附减少皮质血流并损害阿尔茨海默病小鼠模型中的记忆功能”，发表在Nature Neuroscience上。

该论文的共同主要作者是现任哈佛医学院博士后研究员的Jean Cruz-Hernandez博士和Schaffer-Nishimura实验室的研究员Oliver Bracko。

Schaffer说，这篇论文是大约十年研究，数据收集和分析的结晶。它开始于一项研究，其中西村试图将凝块放入阿尔茨海默氏症小鼠大脑的血管中以观察其效果。

“事实证明......我们试图引发的阻塞已经存在，”她说。“这有点改变了研究 - 这是一种已经发生的现象。”

最近的研究表明，脑血流不足是痴呆症最早可检测的症状之一。

“我们所做的是确定导致阿尔茨海默病模型中脑血流量减少的细胞机制，即中性粒细胞[白细胞]粘在毛细血管中，”Schaffer说。“我们已经证明，当我们阻断导致失速的细胞机制时，我们可以获得改善的血流量，并且与改善的血流相关联可以立即恢复空间和工作记忆任务的认知表现。”

“现在我们已经了解细胞机制，”他说，“鉴别药物或治疗它的治疗方法是一条更为狭窄的道路。”

该团队已经确定了大约20种药物，其中许多已经获得FDA批准供人类使用，这些药物具有痴呆治疗的潜力，现在正在阿尔茨海默氏症小鼠中筛查这些药物。

Schaffer表示他“非常乐观”，如果人类和老鼠一样，毛细血管阻断机制起着相同作用，这一系列研究“可能会成为阿尔茨海默病患者完全改变游戏规则的因素”。

该研究由美国国立卫生研究院，阿尔茨海默氏症药物发现基金会，阿尔茨海默氏症艺术被子计划和Brightfocus基金会资助。

New Alzheimer's therapy with brain blood flow discovery?

By discovering the culprit behind decreased blood flow in the brain of people with Alzheimer's, biomedical engineers at Cornell University have made possible promising new therapies for the disease.

You know that dizzy feeling you get when, after lying down for an extended period, you stand up a little too quickly?

That feeling is caused by a sudden reduction of blood flow to the brain, a reduction of around 30 percent. Now imagine living every minute of every day with that level of decreased blood flow.

People with Alzheimer's disease don't have to imagine it. The existence of cerebral blood flow reduction in Alzheimer's patients has been known for decades, but the exact correlation to impaired cognitive function is less understood.

"People probably adapt to the decreased blood flow, so that they don't feel dizzy all of the time, but there's clear evidence that it impacts cognitive function," said Chris Schaffer, associate professor of biomedical engineering at Cornell University.

A new study from the joint lab of Schaffer and associate professor Nozomi Nishimura, offers an explanation for this dramatic blood flow decrease: white blood cells stuck to the inside of capillaries, the smallest blood vessels in the brain. And while only a small percentage of capillaries experience this blockage, each stalled vessel leads to decreased blood flow in multiple downstream vessels, magnifying the impact on overall brain blood flow.

Their paper, "Neutrophil Adhesion in Brain Capillaries Reduces Cortical Blood Flow and Impairs Memory Function in Alzheimer's Disease Mouse Models," published in Nature Neuroscience.

The paper's co-lead authors are Jean Cruz-Hernandez, Ph.D., now a postdoctoral researcher at Harvard Medical School, and Oliver Bracko, a research associate in the Schaffer-Nishimura Lab.

The paper, Schaffer said, is the culmination of approximately a decade of study, data gathering and analysis. It began with a study in which Nishimura was attempting to put clots into the vasculatures of Alzheimer's mouse brains to see their effect.

"It turns out that ... the blockages we were trying to induce were already in there," she said. "It sort of turned the research around -- this is a phenomenon that was already happening."

Recent studies suggest that brain blood flow deficits are one of the earliest detectable symptoms of dementia.

"What we've done is identify the cellular mechanism that causes reduced brain blood flow in Alzheimer's disease models, which is neutrophils [white blood cells] sticking in capillaries," Schaffer said. "We've shown that when we block the cellular mechanism [that causes the stalls], we get an improved blood flow, and associated with that improved blood flow is immediate restoration of cognitive performance of spatial- and working-memory tasks."

"Now that we know the cellular mechanism," he said, "it's a much narrower path to identify the drug or the therapeutic approach to treat it."

The team has identified approximately 20 drugs, many of them already FDA approved for human use, that have potential in dementia therapy and are screening these drugs in Alzheimer's mice now.

Schaffer said he's "super-optimistic" that, if the same capillary-blocking mechanism is at play in humans as it is in mice, this line of research "could be a complete game-changer for people with Alzheimer's disease."

This research was funded by the National Institutes of Health, the Alzheimer's Drug Discovery Foundation, the Alzheimer's Art Quilt Initiative, and the Brightfocus Foundation.

Story Source:
Materials provided by Cornell University. Note: Content may be edited for style and length.

Journal Reference:
Jean C. Cruz Hernández, Oliver Bracko, Calvin J. Kersbergen, Victorine Muse, Mohammad Haft-Javaherian, Maxime Berg, Laibaik Park, Lindsay K. Vinarcsik, Iryna Ivasyk, Daniel A. Rivera, Yiming Kang, Marta Cortes-Canteli, Myriam Peyrounette, Vincent Doyeux, Amy Smith, Joan Zhou, Gabriel Otte, Jeffrey D. Beverly, Elizabeth Davenport, Yohan Davit, Charles P. Lin, Sidney Strickland, Costantino Iadecola, Sylvie Lorthois, Nozomi Nishimura, Chris B. Schaffer. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models. Nature Neuroscience, 2019; DOI: 10.1038/s41593-018-0329-4