阿尔茨海默病：我们对其病因的认知一直有误 | 卡尔·赫鲁普教授

它影响突触发生，即神经元之间连接的形成。

It impacts synaptogenesis, the formation of connections between neurons.

所以它在发育过程中扮演着重要角色。

So it has a huge role in development.

我们的研究表明，它在正常神经元功能中还具有我们称之为稳态调节的作用。

And what our work showed was that it also has what we could call a homeostatic role in normal neuronal function.

当神经元活动略高于正常水平时，这种活动会触发淀粉样前体蛋白水平升高，进而导致轴突结构发生改变，使其更难产生电信号。

So when a neuron gets a little bit more active than normal, that activity triggers an increase in the levels of the amyloid precursor protein, and that increase causes the structure of the axon to change in such a way that it becomes less easy to create, an electrical signal.

而且

And

它几乎就像一个调节器。

that becomes almost like a governor.

所以如果活动过度，APP就会上升。

So if you get too much activity, APP goes up.

APP是淀粉样前体蛋白的缩写。

APP is the abbreviation for amyloid precursor protein.

APP上升会改变轴突结构，从而使神经元恢复平静。

APP goes up, it changes the axon structure, and that quiets the neuron back down.

所以这是一种保护机制。

So it's a a protective mechanism.

就像恒温器一样。

It's like a thermostat.

像个恒温器。

Like a thermostat.

这非常有趣。

That's very interesting.

我认为很多人对APP（淀粉样前体蛋白）感兴趣，部分原因是它的突变是家族性疾病的遗传驱动因素，另外还有早老素1和2的突变，它们影响γ分泌酶的活性，这种酶会切割APP。

I think a lot of people have been interested in APP, amyloid precursor protein, in part because mutations in it are genetic drivers of the familial form of the disease, along with mutations in a couple of other genes, presenilin one and two, which influence the activity of one of the enzymes, gamma secretase, that cuts APP.

这让我想起你之前的一些评论，因为在我看来，APP和早老素，或许还有淀粉样蛋白本身，以及为模拟淀粉样变性而开发的小鼠模型，与家族性疾病形式最为相关。

This brings to mind some of your comments earlier because it seems to me that APP and the presenilins, and perhaps amyloid in general, and the mouse models that have been developed to mimic amyloidosis are most relevant to the familial form of the disease.

你觉得这个评论公允吗？

Do you think that's a fair comment?

哦，我觉得这非常公平。

Oh, I think it's totally fair.

正如我刚才所说，我们正在提交发表的细胞层面研究表明，它们对神经网络功能乃至结构会产生截然不同的影响。

And as I was saying, the work that we're just now submitting for publication at a cellular level argues that they have very different impacts on the function and even the structure of neuronal networks.

所以是的，我认为它们是截然不同的情况。

So, yes, I think they're very different conditions.

这印证了我先前的观点——无论是APP基因还是早老素基因突变，这些遗传性阿尔茨海默症从胚胎形成起就会影响大脑。

And I think it plays into what I said before, which is that these genetic forms of Alzheimer's, whether the mutation is in the APP gene or in the presenilin gene, they're going to impact the brain from conception.

整个大脑发育过程（对其最终功能形成至关重要）都将在APP基因突变的环境中进行。

So the entire developmental process of the brain, which is very, very formative in its ultimate ability to function, will have been undertaken in the context of having a mutant APP gene.

我们的生物机制非常精妙，通常都能绕过这类问题。

Now our biologies are very clever, and they can almost always work around a problem like that.

但这种代偿机制会使大脑在其他方面变得脆弱，这些影响可能不会立即显现，但会随着大脑衰老逐渐显露。

But the workaround leaves the brain vulnerable in other ways, that may not be apparent right away, but will be apparent as the brain ages.

关于β淀粉样蛋白（APP基因分解产生的肽段），学界对其是否完全有害存在分歧。

Regarding amyloid beta, these peptides that APP gets cut into, people have conflicting opinions about whether all amyloid is bad.

一些敢于质疑传统的学者提出，淀粉样蛋白很可能在正常生理机能中扮演多种角色。

And some people who are willing to question convention have put forward that amyloid likely has various roles in normal physiology.

正如我们提到的，它存在于每个人的大脑中，有人认为它参与免疫功能等多种生理过程。

As we mentioned, it's present in everybody's brain, and people are pointed to roles in immune function and various other processes.

你认为它在健康大脑中是否具有某些功能？

Do you think that it has some roles in a healthy brain?

你觉得这些功能可能是什么？

What do you think those roles might be?

另外，你认为我们需要区分不同的淀粉样肽吗？

And also, do you think we need to distinguish different amyloid peptides?

它们都是一样的吗？

Are they all made equal?

短肽和长肽有区别吗？

Are shorter peptides different from longer ones?

让我从最核心的问题开始——这种小淀粉样肽是否存在正常功能？

Let me start with the overarching question, which is, is there a normal function for this little amyloid peptide?

我认为答案很可能是肯定的。

And I think the answer is probably yes.

我有一位朋友兼同事阿尔贝托·埃斯佩，他坚定支持一个观点：阿尔茨海默病的问题实际上是较长形式的淀粉样肽（即Aβ42）含量过少。

I have a friend and colleague, Alberto Espe, who is a very strong partisan of the idea that, in fact, the problem in Alzheimer's is too little of the amyloid peptide that is one of the longer forms.

之所以叫Aβ42，是因为42代表该肽链中的氨基酸数量。

It's Abeta 42, because the 42 stands for the number of amino acids in that peptide.

支持这一观点的证据相当有力，包括针对单克隆抗体进行的一些临床试验。

And the evidence for it is is somewhat compelling, including some of the clinical trials that were done for the monoclonal antibodies.

那么Aβ是否具有正常生理功能？

So does Abeta have a a normal physiological function?

我们早就知道它具有正常生理功能。

We knew it had a normal physiological function.

它绝对是一种突触调节剂。

It is absolutely a synaptic modulator.

至于这如何融入大脑的正常功能机制，我认为我们尚未完全弄清楚。

How that folds into the normal function of the brain, I don't think we're entirely clear.

它在阿尔茨海默病中起作用吗？

Does it have a role in Alzheimer's?

如果espe是对的，那么确实如此，因为它的不足彻底颠覆了我们所有治疗阿尔茨海默病的方法。

If espe is right, then it actually does because there's not enough of it, which turns all of our Alzheimer's therapeutic approaches on their head.

但你知道，数据就是数据。

But, you know, data's data.

现在当然，我忘记了你问题的第二部分是什么，所以我们继续吧。

And then now, of course, I'm forgetting what the second part of your question was, so let's move on.

问题的第二部分是

The second part of the question was

我偶尔可以打这张老牌，所以我要在这里第一次打出来。

I'm allowed about to play the old card occasionally, so I'll I'll I'll play it for the first time here.

我认识到认知刺激对缓解阿尔茨海默病的重要性。

Well, I recognise the importance of cognitive stimulation to mitigating Alzheimer's.

所以我的目标是最大化这次对话的认知负荷。

So my goal is to maximise the cognitive load of this conversation.

我很感激，是的，

And I appreciate Yeah,

非常感谢。

thank you very much.

是的，问题的第二部分是关于不同肽类及其效果差异的。

Yeah, the second part of the question was just about the different peptides and whether they differ in their effects.

我认为

I think

你之前已经多少暗示过这一点了。

you had you somewhat alluded to that anyway.

我确实提到过这个。

I did touch on that.

是的。

Yeah.

它们确实很重要。

They do it does matter.

在你的书中，你详细描述了淀粉样蛋白级联假说如何未能通过一些关键测试。

In your book, you at length describe how the amyloid cascade hypothesis has failed some critical tests.

你能简要说明这些测试是什么吗？

Can you briefly describe what these tests are?

我想你重点提到了三个

I think you highlight three of

两个关键点是这个。

The the two critical ones are this.

如果假说成立，那么当你将淀粉样蛋白注入健康人的大脑时，应该会引发阿尔茨海默病。

If the hypothesis is true, then if you add amyloid to the brain of a healthy person, you should create Alzheimer's disease.

这将是该假说的一个预测。

That would be a prediction of the hypothesis.

这根本不符合事实。

That is fundamentally not true.

因此，30%认知功能完全正常的个体——那些过着最佳正常生活的人，如果年龄超过65岁，他们有30%的几率携带与阿尔茨海默病（至少早期阶段）诊断相符的淀粉样蛋白负担。

So thirty percent of perfectly cognitively intact individuals, people walking around living their best normal life, if they're over the age of 65, they have a thirty percent chance of having amyloid burdens that would be consistent with the diagnosis of at least early stages of Alzheimer's disease.

他们是否面临更高的阿尔茨海默病患病风险？

Do they have, an increased risk of developing Alzheimer's?

确实如此，但风险增幅并不显著。

Yes, they do, but the increased risk is not dramatic.

无论如何，这些个体还能再活五年，其中仅半数会发展成某种形式的痴呆症。

And in any event, those individuals can live for another five years, only half of them will progress into some form of dementing illness.

因此至少可以说，淀粉样蛋白的存在并不像是一种生物机制。

So at the very least, the presence of amyloid, it doesn't strike one as a biological mechanism.

一个风险因素？

A risk factor?

也许吧。

Perhaps.

但如果说淀粉样蛋白沉积可以蛰伏五年，之后才有50%概率诱发痴呆，在我看来这恰恰证明了假说的失败。

But to say that amyloid deposits can wait five years before having a fifty percent chance of triggering a dementia, that's to me, that's a failure of the hypothesis.

小鼠实验数据也印证了这点——我们可以通过基因改造让小鼠大脑充满淀粉样蛋白，它们确实会出现记忆障碍，但完全不会表现出阿尔茨海默病的临床症状。

And then the mouse data suggests the same, which is that we can, take mice and engineer them so they produce boatloads of amyloid and fill their brains with it, And they do end up with memory problems, but they don't end up with anything resembling the clinical symptoms of Alzheimer's disease.

正如我在书中强调的，更关键的是：清除这些淀粉样蛋白后，小鼠能完全康复，但人类患者却不会。

And as I point out in the book, more importantly, if you do things to get rid of that amyloid, the mice get better, and they get a 100% better, and that does not describe the human condition.

所以即便清除人脑中的淀粉样蛋白，患者病情也不会好转——实际上最新单克隆抗体临床试验表明病情仍在持续恶化。

So if we get rid of amyloid in the human brain, people don't get better, and in fact, the recent monoclonal clinical trials suggest they continue to get worse.

这是第一个验证点。

So that's trial number one.

第二个验证点是：如果我们清除脑内淀粉样蛋白，理应能预防阿尔茨海默病。

Trial number two is if we take amyloid out of the brain, we should prevent Alzheimer's.

神经退行性疾病之所以棘手，是因为一旦损伤形成就无法逆转，但如果淀粉样蛋白级联假说成立，我们应该能阻止病情恶化，因为进一步损伤会被阻断。

Neurodegenerative diseases are nasty because they can't you can't reverse damage once it's done, but you should be able to stop the disease if the amyloid cascade hypothesis is correct, because further damage should be blocked.

事实上，纵观多年来完成的临床试验，我们已能通过多种策略大幅减少甚至基本清除大脑中的淀粉样蛋白。

And in point of fact, if you look over the years at the clinical trials that have been done, we've been able to reduce or virtually eliminate amyloid from the brain using various strategies.

而在大多数情况下——确切地说是所有病例中——患者病情仍在持续恶化。

And in most cases, actually in all cases, people continue to get worse.

在极少数病例中（不到5%），通过显著降低淀粉样蛋白水平，我们可略微减缓恶化速度，但患者状况并未改善。

In a tiny fraction of the cases, less than five percent, with very significant amyloid reduction, we can slightly slow the rate of decline, but they don't get people don't get better.

因此这未能通过第二项验证。

So that's a failure of the second test.

第三项验证本应是阻止肽链形成就能遏止疾病发展，但同样未能奏效。

The third test would be that you should be able to block the formation of the peptide, and stop the disease, and that that doesn't work either.

此刻很难保持礼貌，因为我想说的是：我们何必执着于这个假说？

It's always hard to be polite at this point because what I wanna say is, so why are we bothering with this hypothesis?

不过礼貌的说法是：好吧。

But the polite way to say that is, okay.

淀粉样蛋白可能对整体病理有所贡献，但我们必须重新定位其作用并予以清除。

There may be some biological contribution to the total picture from amyloid, But we're going to have to put it in its place, and we're going to have to remove it.

以下是我论证的关键部分：

And here is the key part of my argument.

我们必须将其从疾病的生物学定义中剔除，更必须将其从现行临床定义中移除。

We're going to have to remove it from the biological definition of the disease, and we're certainly going to have to remove it from the definition of the disease, which is where it stands right now.

针对您早前提到的观点，需要说明的是：基线淀粉样蛋白高负荷带来的风险增幅，大致相当于携带一份APOE4等位基因。

To put something into perspective that you mentioned earlier, I think the increased risk that's associated with the high amyloid burden at baseline is roughly equivalent to carrying one copy of the APOE four allele.

这是正确的吗？

Is that correct?

这是正确的。

That is correct.

是的。

Yep.

是的。

Yep.

大约三倍的风险增加，是这样吗？

Roughly a threefold increased risk, something like that?

对。

Yeah.

具体数字可能有所不同。

The numbers may vary.

自从写完那本书后，我就没再深入研究这些细节了。

I haven't gone back in into the weeds since I wrote the book.

也许数字已经变了。

Maybe the numbers have changed.

但大致没错，风险确实低于ApoE4纯合子携带者。

But that's roughly correct, that the risk is less than being an ApoE4 homozygote.

那么是否可以说，每位严重阿尔茨海默病患者的大脑中都会有大量淀粉样蛋白？

And is it fair to say that every patient that has severe Alzheimer's disease will have a lot of amyloid in their brain?

这个问题其实和定义纠缠不清——因为按照定义，如果患者临床表现与阿尔茨海默病完全一致但大脑没有淀粉样蛋白沉积，那严格来说就不能诊断为阿尔茨海默病。

Well, that, of course, gets all knotted up in the definition, because by definition, if they have a clinical picture a a clinical a set of clinical symptoms that looks exactly like Alzheimer's disease, but they don't have amyloid deposits in their brain, by definition that was not Alzheimer's disease.

那么如果我们重新定义，排除淀粉样蛋白，那这个说法还成立吗？

So if we rework definition to exclude the amyloid, then would that be true?

那么我认为我们可以查阅临床文献发现，当神经科医生诊断阿尔茨海默病时，病理学家或放射科医生会观察是否存在淀粉样蛋白。

Well, then I would say we can go to the clinical literature and find out that when a neurologist diagnoses Alzheimer's, the pathologist gets to look at, or the radiologist gets to look at the presence or absence of amyloid.

而通过其缺失情况，神经科医生有15%的误诊率。

And by its absence, the neurologist was wrong fifteen percent of the time.

但我将此视为神经科医生诊断正确的证据，实际上15%的阿尔茨海默痴呆症患者并没有淀粉样蛋白沉积。

But I take that as evidence that the neurologist was right, and in fact, fifteen percent of Alzheimer's dementia does not have amyloid deposits.

我这么问是因为我在考虑tau蛋白缠结的问题。

The reason I asked that is because I was thinking about tau tangles.

嗯。

Mhmm.

事实上它们似乎——不过这可能也是阿尔茨海默病定义方式的另一个产物——相比淀粉样蛋白，对阿尔茨海默病的特异性较低。

And the fact that they seem, but maybe this is another product of the way that Alzheimer's is defined, to be less specific to Alzheimer's compared with amyloid.

如果我们观察不同的神经退行性疾病，会发现tau蛋白缠结也出现在其他多种疾病中。

So if we look across different neurodegenerative condition, then we see tau tangles popping up in various other disorders too.

这个说法合理吗？

Is that a fair statement?

这是个合理的说法。

That is a fair statement.

是的。

Yes.

你认为tau蛋白缠结在阿尔茨海默病病理生理学中可能产生哪些影响（如果有的话）？

What do you think are some of the potential effects of the tau tangles in Alzheimer's pathophysiology, if any?

好问题。

Good question.

我发现tau蛋白缠结在生物学上与疾病进程的联系比淀粉样蛋白沉积更为紧密。

I find the tau tangles to be much more biologically entwined with the disease process than the amyloid deposits.

正如我之前所说，我们可以在小鼠脑中注入淀粉样蛋白，它们会出现短期记忆问题，但不会发生神经退行性病变。

So I said before we can fill a mouse's head with amyloid, and they have a few short term memory problems, but no neurodegeneration.

但tau蛋白的情况并非如此。

That's not true for tau.

如果我们建立包含某些tau蛋白突变的遗传模型——这些突变会导致神经退行性病变——就能观察到神经退行性病变，且症状表现更为相似。

If we actually create genetic models that incorporate some of the mutations of tau that lead to neurodegeneration, we get neurodegeneration, and the symptoms begin to look much more similar.

虽不完美，但相比淀粉样蛋白相关病变，这些症状的相似度要高得多。

Not perfect, but they look much more similar than do their amyloid cousins.

因此tau蛋白确实有影响，但正如你所说（我认为这是正确的），这些沉积物并非疾病特异性标志。

So tau contributes, but as you said, and I think it's true, those deposits are not disease specific.

它们也存在于其他病症中。

They're found in other conditions.

编码tau蛋白的基因突变会导致什么后果？

What do mutations in the gene that encodes tau cause?

它们主要与哪些神经退行性疾病相关？

Which neurodegenerative diseases do they contribute to most?

这当然取决于具体突变类型，但它们与一种称为额颞叶痴呆的痴呆症相关。

So it depends on the mutation, of course, but, they're linked to a form of dementia known as frontotemporal dementia.

最近还有一项非常激动人心的科学发现：它们与肌萎缩侧索硬化症（ALS，即卢·格里克病）几乎存在连续性关联。

And more recently, and I think in a very exciting scientific advance, they're also linked in almost a continuum with amyotrophic lateral sclerosis, or ALS, or Lou Gehrig's disease.

与神经退行性疾病密切相关，这些疾病在症状和生物学基础上都与阿尔茨海默病不同。

So very involved in neurodegenerative illnesses, which both by symptoms and by their underlying biology are different from what goes on in Alzheimer's disease.

有意思。

Interesting.

我们之前稍微讨论过脑萎缩，这与大脑中某些细胞体积或数量的减少有一定关联。

We spoke a little bit about brain atrophy earlier, and that is somewhat related to the loss of the volume and or numbers of certain cells in the brain.

其中可能包括神经元。

Those can include neurons.

你认为这种脑容量损失对阿尔茨海默病的影响有多大？

How much do you think that that brain volume loss contributes to Alzheimer's?

我知道它也是其他各种问题的下游表现。

I know that it's also downstream of various other issues.

但你认为从根本上说，这是阿尔茨海默病的重要驱动因素吗？

But do you think that fundamentally, that's a really important driver of Alzheimer's?

哎呀。

Oh, boy.

这是个非常好的问题。

Good a very good question.

让我以科学家的身份说，答案是既肯定又否定。

And let me be a scientist for a moment and say the answer is yes and no.

是的。

Yes.

如果失去三分之一的大脑，想要保持正常功能会困难得多。

It's much harder to have a normal functioning brain if you take away a third of it.

然而我们的大脑具有极强的可塑性，让我这样解释。

And yet our brains are very, very plastic and are let me put it this way.

我认为，就像我们在阿尔茨海默病中看到的那样，即使失去四分之一的脑容量，大脑本身也能应对这种情况。大脑的网络特性足够强大，虽然可能会出现一些功能上的小问题，但整体功能仍能保持正常。

I think the loss of a quarter of the brain volume, as we see in Alzheimer's, I think in and of itself the brain could deal with that, that the network properties of the brain, are robust enough that you may have some loose ends hanging out, but that the overall function of the brain would be just fine.

所以当我说是或不是时，我的意思是灰质减少会给神经网络带来压力以维持功能，但这本身并不会导致疾病。

So when I say yes or no, what I mean by that is that having less gray matter is going to strain the network, to maintain function, but does not by itself cause the disease.

我们是否了解网络变化轨迹与大脑结构变化之间的关系？

Do we know much about how the trajectory of network changes relates to change in brain structure?

不，我们不了解。

No, we don't.

换句话说，这是个典型的先有鸡还是先有蛋的问题。

In other words, it's a huge chicken and egg problem.

那么

So

是功能缺失导致神经元死亡，还是神经元死亡导致功能缺失？

does the lack of function lead to the death of neurons, or does the death of neurons lead to lack of function?

我认为这个问题没有明确答案。

I don't think there's a clear answer to that.

你们实验室重点研究了非计划性细胞周期事件在神经元损失中的作用。

Your lab's focused quite a lot on the roles of unscheduled cell cycle events in the loss of neurons.

你能概括一下什么是细胞周期吗？

Can you summarize what the cell cycle is?

然后你发现了它与神经元存活率之间有什么关联？

And then what you found regarding how that relates to the viability of neurons?

这个问题我得承认最近没怎么研究，但自研究生时期起就一直让我着迷。

That it's a problem which I have to say I I have not worked on recently, but it's one that has intrigued me since I was a graduate student.

事实证明，神经元是这方面的经典案例，但并非唯一例证。

So it turns out that and neurons are a classic example of this, but they're not the only example.

在胚胎发生过程中，随着我们身体的发育，某些细胞类型会决定最终分化方向。

That as our bodies develop during embryogenesis, during during our developmental process, Certain cell types make the decision to what terminally differentiate.

这对神经元至关重要，因为它们需要形成极其复杂的细胞结构。

And that's important if you're a neuron because you're gonna have to develop a very, very complex cellular structure.

你需要这些精密的树突分支。

You need these very elaborate dendritic branches.

你需要能延伸数百倍于细胞体长度的轴突。

You need a very long axon, that can project hundreds of times the size of your cell cell body.

因此组装这种结构是一项重大工程壮举。

So it's a major engineering feat to put that together.

按事后逻辑来看，这时最不需要的就是细胞分裂这种会破坏结构的进程。

The last thing you need, and this is retrospective logic, but it would seem like the last thing you would need at that point is the structurally disruptive process of having to divide into two cells.

那么该如何处理所有这些结构呢？

So what do you do with all that structure?

好吧。

Okay.

你可以分裂出一个小细胞并称之为细胞分裂，但那样原有结构就不复存在了。

You can butt off a little cell and call that cell division, but then you don't have the structure anymore.

最后你得到的只是个小不点。

So all you've got is a a little p.

作为分化过程的一部分，神经元以及其他细胞会经历这一阶段，从而丧失进一步分裂的能力。

So as part of that differentiation process, neurons, and as I say other cells go through this, become incapable of further cell division.

正如我常说的，人在一岁时就已拥有此生所有的神经元。

As I often say, you get all of the neurons you're ever going to have by the time you're one year old.

此后，你唯一能做的就是不断失去它们。

And after that, all you can do is lose them.

这对我们的大脑是个巨大的生物学难题，因为这意味着一旦失去细胞就无法再生。

That that's a huge biological problem for our brains because it means that if you do lose a cell, it cannot be replaced.

但我关于细胞周期研究的理论基础是：虽然上述观点成立，但细胞永远不会忘记其进化起源，面对压力时往往会试图通过分裂来摆脱困境。

But the logic behind my cell cycle work was that that may be true, but cells never forget their evolutionary origin and will respond to stress very often by trying to divide to get out of the situation.

在我看来，神经元也不例外。

And neurons are, in my opinion, no different.

因此在阿尔茨海默病的压力下，细胞会启动细胞周期过程。

So during the stress of Alzheimer's disease, cells will initiate a cell cycle process.

它们会开始合成细胞分裂所需的蛋白质。

They will begin to form synthesize the proteins needed to go through cell division.

它们实际上会开始复制DNA，仿佛准备分裂，但被永久阻断，无法进入真正的分裂阶段实现一分为二。

They will actually start to duplicate their their their DNA as if they were going to divide, but they are permanently blocked, and they cannot proceed to the stage where they are able to go through a cell division process and create two cells from one.

我最初提出的观点是：它们非但未能分裂，反而启动了细胞死亡程序。

The original argument I made was that instead of dividing, they initiate a cell death process.

我的假说认为，这正是阿尔茨海默病神经退行性病变的潜在机制。

And my hypothesis was that that underscored, underlay the neurodegenerative process in Alzheimer's disease.

这个理论或许成立，但最近出现了新发现：那些神经元实际上并未真正死亡。

That may be true, but recently a wrinkle on that idea has come forward, and that is that those neurons don't actually die.

在生物学的一个复杂环节中，这些神经元激活了被称为细胞衰老的过程。

And in a complicated bit of biology, those neurons activate a process known as senescence.

我们认为这种衰老过程是细胞的一种特性，部分功能在于预防癌症。

And that senescence process is a property of our cells that we believe functions in part to prevent cancer.

因为当细胞衰老启动时，其特征之一就是细胞分裂被完全阻断。

Because when senescence kicks in, one of its features is that cell division is completely blocked.

所有这些仍与现有数据吻合。

So all of that still fits with the data.

这些细胞并不会死亡。

The cells don't die.

它们只是进入了衰老过程。

They simply enter the senescence process.

我们确实有证据证明这一点。

And we do have evidence that that's true.

但随后出现了极其反常的转折——我目前的假设是：衰老细胞最终并不会死亡。

But then in a in a really bizarre twist, my current hypothesis is that the senescent cells in the end don't die.

但由于其衰老状态，它们会分泌某些因子

But because of their senescence, they secrete factors

作用于其他细胞。

to of other cells.

触发其他细胞的死亡。

Trigger the death of other cells.

天啊。

Oh, man.

我要说的是，早在2007年，我就写过一篇综述，至少提出了这种可能性。

And I'm I'm going to say that as far back as 2007, I wrote a review in which I at least laid out that this was a possibility.

而我们近期的数据表明，实际情况正是如此。

And our more recent data suggests that this is actually what's going on.

所以这些衰老细胞正在产生所谓的衰老相关分泌表型？

So those senescence cells are producing the so called senescence associated secretory phenotype?

正确。

Correct.

这锅大杂烩般的炎症因子会对邻近细胞造成损害，没错。

This hot potch of different inflammatory chemicals that then take their toll on nearby cells Correct.

并导致这些细胞在可能形成恶性循环的过程中流失。

And drive the loss of those cells in what can become a fissure cycle.

正确。

Correct.

真糟糕。

Nasty.

我们接着讨论另一种细胞类型。

Moving on to a different cell type.

神经胶质细胞有很多种类。

There are lots of types of glial cells.

其中一种是少突胶质细胞。

One of these is the oligodendrocyte.

你长期以来对这些细胞非常感兴趣。

You've been very interested in these cells for some time.

它们对髓鞘形成至关重要，髓鞘形成本质上是在细胞周围包裹这种脂肪鞘——髓磷脂，以加速电化学信号的传递，从而提高大脑向邻近结构传递信息的速度。

They are instrumental to myelination, which is basically wrapping myelin, this fatty sheath around cells in order to speed the transmission of electrochemical signals, speeding the rate at which the brain can pass information onto nearby structures.

我认为你在推动这些特定细胞的重要性方面遥遥领先。

And I think you are way ahead of the curve in pushing the importance of these particular cells.

你能多谈谈它们吗？为什么你认为它们对阿尔茨海默病如此重要？

Can you tell us a little bit more about them and why you think they are so important to Alzheimer's?

好的。

Okay.

在开始之前，我要特别感谢我认为是推动少突胶质细胞或髓鞘形成对阿尔茨海默病贡献的先锋人物。

So before I do, let me give you a shout out to the person I think was the point of the spear in pushing the oligodendrocyte or myelination contributions to Alzheimer's.

那就是乔治·巴特扎基斯。

That would be George Bartzakis.

他主要从事影像学研究而非细胞生物学本身，但他坚信痴呆症最可靠的症状之一就是相关区域神经纤维束中髓磷脂的缺失。

He worked with imaging, rather than with the cell biology itself, but was, just passionate that one of the most reliable symptoms of a dementing illness is the loss of myelin in the tracks that service that area.

话虽如此，确实，我一直对髓磷脂和产生它的少突胶质细胞都深感着迷。

Having said that, yeah, I I have been fascinated by, both the myelin and the oligodendrocytes, the cells that create it.

当我说'两者'时，是因为髓磷脂作为一种物理结构，对大型神经元极为有益。

And when I say both, I say that because the myelin, just as a physical structure, is extremely helpful to larger neurons.

原因在于通过绝缘神经元，它们使电信号的传递在能量上更加高效。

And the reason is that by insulating the neurons, they make the transmission of electrical signals much more efficient energetically.

因此神经元会花费大量时间泵送离子以保持自身处于可被电激活的状态。

So the neuron spends a lot of its time pumping ions to keep itself in a state where it can be activated electrically.

而这些离子泵需要消耗化学能。

And those pumps cost chemical energy.

能量的通用货币是ATP。

The currency of energy is ATP.

所以它们消耗大量ATP。

So they they they cost a lot of ATP.

通过在轴突上覆盖一种油脂物质阻止离子流动，让所有离子泵得以休息，从而节省大量ATP。

By coating the axon with a sort of a oily substance that won't allow ions to flow, it lets all those pumps take a break, and it saves a lot of ATP.

这是结构上的帮助，但还有化学层面的帮助。

That's a structural help, but there's also a chemical help.

这些少突胶质细胞还会产生轴突所需的营养物质，而轴突反过来也为少突胶质细胞提供物质。

So these oligodendrocytes also create nutrients that the axons use, and the axons in turn provide stuff to the oligodendrocytes.

因此存在非常强烈的细胞间相互作用——至少我认为这些相互作用的失效在很大程度上导致了我们称之为阿尔茨海默病的症状。

So there's a real strong cell cell interaction that, at least in my way of thinking, the failure of those interactions contributes in major ways to the symptoms we recognize as Alzheimer's disease.

这里再次强调，就像tau蛋白一样，我们讨论的并非阿尔茨海默病特有的现象。

And here again, like tau, we're not talking about something that is unique to Alzheimer's disease.

我们在其他神经退行性疾病中也观察到髓鞘异常的存在。

So we've looked in other neurodegenerative diseases, and myelin abnormalities are involved there as well.

我想其中最典型的就是多发性硬化症吧。

I suppose the most obvious of those is MS.

是的。

Yes.

但还包括不太明显的疾病，比如我正在研究的这种罕见共济失调毛细血管扩张症。

But also ones that are less obvious, like this rare ataxia telangiectasia that I work on.

这是DNA损伤修复通路中某部分发生了突变。

It's a mutation in a part of the DNA damage repair pathway.

那些人和那些老鼠都遭受着髓鞘和少突胶质细胞的缺失。

Those people and those mice suffer from a loss of myelin and from oligodendrocytes.

你是如何发现这种共济失调形式的？

How did you come to that form of ataxia?

是通过少突胶质细胞吗？

Was it through the oligodendrocyte?

不是。

No.

那是后门途径。

That was backdoor.

曾经，我实际上是一名发育生物学家。

Once upon a time, I was actually a developmental biologist.

我研究模式形成，重点是 cerebellum（小脑）。

I worked on pattern formation, and my focus was on the cerebellum.

事实证明，这种被称为ATM的特殊DNA修复蛋白缺失时，会导致小脑质量的严重损失。

And it turns out that this particular DNA repair protein known as ATM, when it's missing leads to a really profound loss of cerebellar mass.

所以我最初是因为它在小脑发育和维持中的作用而对它产生兴趣的。

So I was interested in it from its role in cerebellar development and maintenance.

但当我转向研究阿尔茨海默病时，我仍然保持着对DNA损伤的兴趣，其中一个原因是未修复DNA损伤的积累似乎是衰老过程的驱动力。

But then when I made the shift to Alzheimer's disease, I maintained an interest in DNA damage, and one of the reasons I maintained it was because the accumulation of unrepaired DNA damage does seem to be a driver of the aging process.

因此，这个我最初因为会损害小脑而研究的ATM蛋白，由于它能保护神经元DNA的完整性，一直让我很感兴趣。

So this protein, ATM, that I started working with because it kills the cerebellum, has continued to interest me because it helps keep the DNA of our neurons intact.

我们肯定会再回到DNA损伤和基因组不稳定性这个话题的。

We will come back to DNA damage and genomic instability, I'm sure of that.

不知道你有没有看到前几天斯坦福大学的托尼·威斯凯瑞发布的一项分析。

I wonder if you saw an analysis that came out a few days ago by Tony Whiskarey, who's at Stanford.

你熟悉他的工作吗？

Are you familiar with his work?

他目前正在进行蛋白质组学研究，专注于器官衰老时钟。

He's doing all of this proteomic work looking at organ aging clocks at the moment.

是的。

Yep.

他刚刚对英国生物银行进行了一项非常有趣的分析。

And he just did an analysis of the UK Biobank, which is very interesting.

基本上，他们的研究表明，那些大脑异常衰老的人——我认为他们定义为大脑生物年龄比同性别和实际年龄人群平均值高出至少1.5个标准差——患阿尔茨海默症的风险显著增加。

And, basically, their suggestion was that people who have unusually aged brains, which I think they defined as at least one and a half standard deviations above the average brain biological age of people of the same sex and chronological age, have a substantially greater risk of Alzheimer's.

这与携带一个APOE4基因拷贝的风险相当。

It's comparable to carrying one copy of APOE four.

他们通过RNA测序分析，研究了构成大脑生物年龄评估的各种蛋白质的可能来源。

And they did this RNA sequencing analysis to look at the likely origins of the different proteins that made up their assessment of brain biological age.

其中约一半来自少突胶质细胞，我认为这进一步支持了你关注的许多重点。

And about half of those were from oligodendrocytes, which I thought was further support for a lot of your focus.

我想你应该会觉得这个结果很令人满意。

I thought you would have found that satisfying.

我确实非常满意。

I'm very satisfied by it.

没错。

Yeah.

但话说回来，你看，我们得公平些。

But then, you know, look, let let's be fair.

相关性并不等同于因果性。

Correlation does not prove causality.

我在书里反复强调这个观点。

I argue that over and over again in my book.

要知道，以剑求生者，终将死于剑下。

And, you know, live by the sword, die by the sword.

在这里我不得不坚持这个立场。

I'm gonna have to stick with that here.

这强有力地证明少突胶质细胞与衰老的核心生物学机制相关。

It's strong evidence that oligodendrocytes are tied up in the core biology of aging.

我们可以假设它们推动了大脑衰老表型，也可以认为它们只是症状表现。

We could posit that they help drive the brain aging phenotypes, or we could posit that they're a symptom.

但无论如何，这现象很有趣，绝对值得深入研究。

But either way, I think it's interesting and certainly merits further study.

是啊。

Yeah.

我认为很多研究路径都会指向少突胶质细胞。

I think many roads lead to oligodendrocytes.

但该分析最有趣的一点是，他们的估算基于对APOE基因型的调整。

But one of the interesting things about that analysis is that their estimates were based on adjustment for APOE genotype.

我知道你近年做过相关研究，探索该基因型与少突胶质细胞功能及髓鞘形成的关系。

And I know that you've done some work in recent years looking at how that genotype relates to oligodendrocytes and their function and myelination.

你找到了吗？

Have you found?

这是一场复杂的分子舞蹈。

It's it's a complicated molecular dance.

少突胶质细胞通过延伸其膜并包裹少量相邻轴突来制造髓鞘。

So oligodendrocytes create myelin, by extending their membrane and wrapping it around a small number of adjacent axons.

这是一种高度特化的膜结构，专门用于生成髓鞘。

That is a very highly specialized membrane that they use to make the myelin.

我们尚不明确具体原因，可能与膜的曲率有关。

We don't know exactly why, possibly because of its curvature.

这种膜富含胆固醇，而清除胆固醇几乎与形成正常髓鞘相矛盾。

The membrane is very rich in cholesterol, and getting rid of cholesterol is almost incompatible with forming normal myelin.

少突胶质细胞面临的困境是：它们需要大量胆固醇，却难以自主合成全部需求，且随着年龄增长问题会加剧。

The problem that oligodendrocytes have is that they need so much cholesterol that they have trouble making it all themselves, and that trouble gets even worse as they age.

这时另一种脑细胞——非神经元细胞星形胶质细胞便前来救援。

So comes to the rescue from another brain cell type, another non neuronal cell type known as the astrocyte.

这些星形胶质细胞负责合成胆固醇并将其输送给少突胶质细胞。

And these astrocytes make cholesterol and ship it off to the oligodendrocytes.

很好。

Great.

星形胶质细胞面临的难题是：胆固醇完全不溶于水，因此运输需要载体。

The problem that the astrocytes face is that cholesterol is completely insoluble, so shipping it off anywhere requires a transport.

它们使用的运输工具是一种名为载脂蛋白E的脂质载体蛋白。

And the transport that they use is this lipid carrier protein known as apolipoprotein E.

这一切都至关重要，因为APOE基因存在三种亚型，它们仅在一两个氨基酸上存在差异，但这些变化却带来天壤之别。

And that all has relevance because the APOE gene comes in three isoforms that differ in one or two amino acids, but those changes have a huge difference.

因此我们用数字来区分这些亚型。

So we know those isoforms by numbers.

一种称为APOE2，一种称为APOE3，还有一种称为APOE4。

So one is called APOE two, one is called APOE three, and one is called APOE four.

其中APOE3最为常见，它能完美运输胆固醇，完全正常运作。

So APOE three is the most common, and it carries cholesterol just fine, thank you very much.

星形胶质细胞和少突胶质细胞都能保持正常功能。

And astrocytes are happy and oligodendrocytes are happy.

APOE2具有保护作用，但APOE4存在问题——它与胆固醇结合能力较差，因此在运输过程中存在缺陷。

APOE2 is protective, but APOE4 is a problem because it does not bind cholesterol as well, and so it is defective in that transport process.

我们的假说是：胆固醇供应不足是导致阿尔茨海默病中髓鞘丢失的生物学基础之一。

And our hypothesis is that loss of a supply of cholesterol is part of what underlies the biology of the loss of myelin in Alzheimer's disease.

这也与我们观察到的全脑结构变化相吻合。

That also maps to what we see when looking at global brain structure.

携带APOE4基因的老年人大脑白质更少，而正是髓鞘使白质呈现白色。

So APOE4 carriers later in life have less white matter in the brain, and it's the myelin that makes it white.

正确。

Correct.

提到ApoE时听众应该不会睡着，因为我认为多数人都已意识到这是普通人群中导致阿尔茨海默病风险的最大遗传因素。

I don't think people will have fallen asleep when mentioning ApoE just because I think a lot of people already recognize that as being the largest genetic contributor to Alzheimer's risk in the general population.

具体来说，如果携带一个e4等位基因，患病风险大约是33基因型人群的三倍。

And to put some numbers to that, if you carry one copy of the e four allele, then your risk is roughly threefold greater than if you were a three three genotype.

如果你携带两个四型基因，即APOE4/4基因型，那么相比三型基因，患病风险可能增加约十倍。

And if you carry two copies of the four, so if you're APOE four four, then it's probably something like a tenfold increase relative to three three.

是这样吗？

Is that right?

十倍甚至更高。

Tenfold or even more.

是的。

Yeah.

所以这确实非常显著。

So it's really significant.

题外话，但有人认为e4等位基因其实是原始型。

And tangent, but it's thought that the e four allele was actually the wild type.

在某些病原体负荷较高的环境下，它可能在某种程度上具有适应性优势——毕竟我们远古祖先的寿命远不及现代人。

And in certain conditions characterized by higher pathogen loads and so on, it might in some ways be adaptive recognizing that our distant ancestors simply didn't live as long as we do.

自然选择不会淘汰这个基因，因为当APOE4的负面效应显现时，大多数人早已过了生育年龄。

It's not like there's been selection against that because by the time APOE4's negative effects kick in, most of us have stopped reproducing.

所以这没什么大不了的。

So it's no big deal.

ApoE蛋白在脂质运输中发挥作用，这涉及到整体新陈代谢。

ApoE has roles in lipid transport, and that brings up metabolism in general.

你研究中提到的另一个主题是胰岛素抵抗，很多人认为这也是阿尔茨海默病的诱因之一。

Another theme that has come up in your research is that of insulin resistance, which a lot of people speak about as being another contributor to Alzheimer's.

我猜想在自由生活人群中，专门研究大脑内的胰岛素抵抗应该相当困难。

And I imagine that it's quite difficult to look at insulin resistance within the brain specifically in free living people.

这个假设合理吗？

Is that a fair assumption?

这是个合理的假设。

That's a fair assumption.

是啊。

Yeah.

是的。

Yes.

但目前的观点认为，大脑胰岛素抵抗和外周胰岛素抵抗都是阿尔茨海默病的诱因。

But the current thinking is that brain insulin resistance as well as peripheral insulin resistance are both contributors to Alzheimer's.

没错。

Right.

关于这点我们的看法是——我要特别感谢我以前的博士后，现任香港中文大学教授的金超，他真正推动了这项工作。

So our view on this, and I shout out to my former postdoc, now professor at Chinese University of Hong Kong, Kim Chao, who really spearheaded this work.

金超发现血糖升高不仅会引起外周反应，还会让脑细胞对胰岛素产生越来越强的抵抗性。

What Kim found was that the elevation of blood glucose leads to a response, not just in the periphery but in the brain, to make the cells more and more insulin resistant.

通过一个相当复杂的新陈代谢途径，这进而会导致...我们稍后再详述。

And through a fairly complex metabolic pathway, that leads in turn to and we'll get back.

这就是细胞衰老理论的来源。

This is where the senescence argument comes from.

这会导致细胞发出内部求救信号，从而激活衰老程序，使这些细胞衰老。正如我们之前所说，它们可能会无意中向邻近细胞发出信号：是时候结账退房了。

That leads in turn for the cells to send out internal distress signals, which activates the senescence program and leads those cells to senesce, and as we said before, to perhaps inadvertently signal to their neighbors, it's time for you to ask for the check and check out.

对大多数人而言，通过改变生活方式就能有效改善胰岛素抵抗问题。

Insulin resistance is something that is readily amenable to change in most people through lifestyle modification.

正确。

Correct.

我们需要记住这一点，稍后再讨论。

We need to bear that in mind, we'll come back to that later.

但导致胰岛素抵抗的另一个因素是线粒体功能障碍。

But another contributor to insulin resistance is mitochondrial dysfunction.

我的印象是有些人过度关注线粒体了。

And my impression is that some people have become hyper focused on mitochondria.

我读过克里斯·帕尔默的《大脑能量》一书，有时我觉得他过于专注线粒体而忽略了整体，这么说吧。

I've read Chris Palmer's book, Brain Energy, and at times I thought that he missed the forest for the mitochondria, let me put it that way.

显然，它们确实重要。

Clearly, they do matter.

你认为它们对阿尔茨海默病的贡献有多大？你认为它们扮演了多重要的角色？

What do you think their contribution to Alzheimer's is, and and how big a player do you think they are?

我确信这因人而异。

I'm sure that it varies between individuals.

我还没读过他的书，但我个人更倾向于特别强调线粒体的作用。

I mean, haven't I haven't read his book, but I would be tend to be more inclined to promote the role of mitochondria, in particular.

但正如你开头所说，我完全同意，整体代谢才是主要因素。

But as as you started, and I would totally agree, metabolism in general is a major contributor.

神经元中的胰岛素抵抗是其中一部分，但仅是一部分。

And insulin resistance in neurons is part of that, but only part of it.

我在书中指出，并在此特别强调：我们的大脑并非孤立存在。

I mean, I point out in the book, and I would really underscore here, you know, our our brains do not exist by themselves.

我是说，我们的大脑存在于身体中，如果身体其他部分消失，大脑就无法良好运作。

I mean, our our brains live in a body, and the brain doesn't work real well if the rest of the body is gone.

反之亦然，如果大脑消失，我们的身体也无法良好运作。

And the reverse is equally true, our bodies don't work real well if our brains are gone.

但这只是简单说明，我们必须从整个生物体的角度而不仅仅是大脑生物学来思考复杂疾病，这些都至关重要。

But that's just a simple way of saying, look, we have to think about demanding illnesses not just from brain biology, but from organismal biology, and it all matters.

我在书中也强调了这一点。

And I make that point in the book.

但在这里讨论新陈代谢时我要特别强调，因为大脑的代谢特征部分由其内部细胞生物学驱动，但也受胰岛素水平、激素水平以及其他大脑外部代谢物水平的影响。

But I would underscore it here while we're talking about metabolism, because the metabolic features of the brain are going to be driven in part by their own internal cell biologies, but they're also going to be driven by levels of insulin, levels of hormones, levels of other metabolites that are extrinsic to the brain.

这些因素来自外周系统。

They come from the periphery.

而所有这些都会影响大脑功能。

And all of that's going to affect brain function.

坦率地说，所有这些都将是衰老过程的一部分。

And frankly, all of it is going to be part of the aging process.

所以你认为线粒体是关键角色吗？

So you think mitochondria are key players?

让我们回到线粒体这个话题。

So getting back to mitochondria.

是的。

Yeah.

我认为它们是我们细胞的能量工厂。

I mean, think that they're the energy powerhouses of our cells.

它们可能不会直接导致阿尔茨海默病，但我想再次强调，当它们的功能效率逐渐下降时，患阿尔茨海默病的风险确实会增加。

They probably don't cause Alzheimer's disease, but once again, I think as they become less and less able to function at peak efficiency, the risk of Alzheimer's increases.

我认同这个观点：线粒体功能的缓慢退化本身就是衰老过程的核心组成部分，也因此成为阿尔茨海默病主要风险因素的核心组成部分。

I would accept an argument that it is in fact this slow degradation of mitochondrial function that is part and parcel of the aging process itself, and therefore part and parcel of one of the major risks, or the major risk, associated with Alzheimer's disease.

你刚才谈到机体健康对大脑健康的重要性。

You spoke there about how important organismal health is to brain health.

举个例子，大脑需要充足的血液供应，这就涉及到心血管系统。

An example of that is that the brain needs an appropriate blood supply, which brings up the cardiovascular system.

在此基础上，我们可以观察血管网络的密度。

And within that, we can look at the density of the vasculature.

我们可以评估血管功能。

We can look at vascular function.

我们可以检测血脑屏障的有效性等等。

We can look at the effectiveness of the blood brain barrier and so on.

能否谈谈血管健康对大脑健康的重要性？

Can you speak a bit about the importance of vascular health to brain health?

噢，这简直太重要了。

Oh, it's tremendously important.

直到现在，血管性痴呆才真正成为研究热点——这个话题最近非常时髦。

And only now, I think, coming into its own as a topic of study, vascular dementia is very au courant these days.

为什么呢？

Why is that?

因为... 我的意思是，我们终于开始认真对待自己的研究数据了。

Well, because it's just I mean, we're finally listening to our own data.

我在书中甚至指出，绝大多数临床诊断和病理诊断的阿尔茨海默病病例都与血管问题密切相关，血管因素与阿尔茨海默病深度交织。

You know, I even pointed out in the book that some enormous majority of cases of clinically diagnosed and pathologically diagnosed Alzheimer's disease have So vascular it's very tightly integrated with Alzheimer's disease.

我们掌握的临床数据表明，运动是一种重要且有效的干预手段，能够降低阿尔茨海默病的发病风险。

And we have the clinical data, which is that exercise is an important and robust intervention that can reduce Alzheimer's risk.

从药理学模型来看，积极控制血压（将血压维持在120以下）对降低阿尔茨海默病风险具有显著效果。

And to get into a more pharmacological model, aggressive control of blood pressure, keeping pressure below 120 has profound effects on Alzheimer risk.

虽然我们在这个领域起步较晚，但我认为我们正在迎头赶上，逐渐认识到血管因素的重要性。

So we're late to the table, but I think we're playing catch up about the importance of vascular factors.

我认为不仅是缺氧和缺血导致的营养供应不足，更重要的是身体其他器官提供的激素健康状态——这是大脑维持巅峰功能所必需的。

And I would argue it's probably not just hypoxia and ischemia that is a failure of nutrients, But I think that it is the accompanying hormonal health that comes from the other organs of the body that the brain, needs to maintain its peak function.

根据对所谓人群归因危险因素的分析，这本质上也是个供应问题。

It's a supply issue too, based on the analyses that have been done looking at the so called population attributable risk factors.

因此，通过生活方式和整体健康状况的不同组成部分，可以解释痴呆症风险差异的比例。

So the proportion of variance in dementia risk that's explained by different components of lifestyle and general health.

高血压无疑是导致痴呆症的最强风险因素之一。

High blood pressure is certainly one of the strongest risk factors that contribute to dementia.

今天就到这里。

That's all for now.

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