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在阿尔茨海默症研究过程中,大象给了我们什么启示?

Clifton Leaf 2018年08月09日

大象的大脑可能有其他生物机制,让神经细胞历经数十年依旧能全力运转。

有关阿尔茨海默病的研究一直以来都被所谓的“宗教战争”(把相关理论的核心词首字母缩写放在一起,正好是宗教徒的单词——译注)所困扰:“浸礼宗教徒”(BAPtists)坚称由β-淀粉样蛋白(beta-amyloid proteins)形成的斑块会影响并最终杀死神经细胞,从而导致了阿尔茨海默症;“道教徒”(TAUists)认为这一疾病的罪魁祸首是神经纤维缠结——即扭曲的tau蛋白——在神经细胞中堆积;“无神论者”(ATHIEsts)则相信尽管这些都是引发阿尔茨海默症的因素,但其他事情(anything else)可能才是病症恶化的最终元凶。

正如我在最近的文章(“为什么阿尔茨海默病的最新药物让这么多人疑惑不解”)中所说,“浸礼宗教徒”的势力最为庞大,在学术研究和药物研发的前沿都积累了一代人甚至几代人的支持。淀粉样蛋白假说的支持者甚至有了新的生物学模型来解释这个病变过程开始和加速的过程。正如作者劳拉·拜勒在《科学通讯》(Science News)的一篇流畅清楚的特稿中所述,这个观点“明确自洽”。

一般在睡眠时,大脑会不断清理游离的β-淀粉样蛋白(又被称作Aβ),这些是神经细胞自身产生的蛋白质残余。如果睡眠中断,垃圾清理过程也会终止。拜勒写道:“学界越来越多人达成共识:大脑没有机会清理神经细胞产生的全部Aβ,于是它们开始在大脑细胞的缝隙中积聚,就像沟槽里的垃圾一样。如果Aβ积聚得过多,就可能形成斑块,我们认为这最终会导致炎症等问题,促成tau蛋白的形成,后者似乎会摧毁神经细胞,引发阿尔茨海默症。”

确实,借助正子断层扫描技术,我们可以看到只要一晚不睡,即使在健康的大脑中,这种游离的蛋白质也会迅速增加,在特定的大脑区域甚至会多达5%。阿尔茨海默症本身会中断睡眠,这只会加速并加重这一病态循环。不过该理论也有缺陷,其中之一就是先有鸡还是先有蛋的谜题,如拜勒所说:“如果阿尔茨海默症会影响睡眠,又会被睡眠所影响,那究竟哪个在前呢?”

另一个缺陷,或者至少说是干扰因子,在于人们通过在研究性的临床试验,对淀粉样蛋白的清理剂进行过多次测试,但阿尔茨海默症的进程却从未因此终止。正如我最近所说,百健(Biogen)和卫材(Eisai)的抗淀粉样蛋白药物BAN2401最近在第二阶段试验中获得的结果也并未改变这一情况。尽管接受试验性抗体的患者在认知能力上或许有所改善,但结果似乎没有体现出许多人希望甚至预期的效果。

在此之上的另一个重量级问题在于:我们可以把它称为“七吨的谜题”——或是“阿尔茨海默奇异屋中的大象”:为什么大象在年老后不会经历类似的大脑退化?

非洲象(Loxodonta africana)的大脑几乎比人类大三倍,其中约有2,570亿个神经细胞,我们人类只有大约1,000亿个(尽管大象的大部分神经细胞都在大脑皮层之外)。但弗吉尼亚大学(University of Virginia)著名的已退休研究教授迈克尔·加斯唐在他的著作《大象的理智与情感》(Elephant Sense and Sensibility)中写道,暮年大象的记忆力似乎相当惊人。象群的首领记得几十年前曾去过的遥远地点,并会把这些知识传给下一代非洲象。

此外,在我们所知的范围内(毕竟我们很难问大象昨天早餐吃了什么),似乎没什么证据表明老象的智力会出现下滑。迄今为止,我们在少数老象死后解剖的大脑中,也没有找到淀粉样蛋白斑块积聚的证据。

至于睡眠可以清理大脑的理论,在大象身上也不太适用:大体上说,这种生物睡得很少。(一项研究表明,野象每天只睡两小时,被囚禁的大象会睡得长一些。)无论如何,如果大象要在睡觉期间清理任何淀粉样蛋白,那留给它们的时间并不多。

一个可能的解释是大象的大脑可能有其他生物机制,让神经细胞历经数十年依旧能全力运转。

但另一个理论则与机制无关——而是直指大象生活的核心:它们高度社会化。这些动物一生都聚集在一起,有着紧密的家族关系,一代接一代。年迈的大脑依旧保持活跃,是否与此有些关系呢?

事实上,许多研究认为事实或许正是如此。有关人类的几项研究似乎证实,强有力的社会联系会降低老年人出现认知损害的风险,而相反的情况(脱离社会)会让神经退化状况加剧。

不幸的是,这样的证据可能为美国的阿尔茨海默症致死案例增加提供了线索。从2000年至2015年,阿尔茨海默症致死的人数增加了123%。归根结底,这样悲伤的数据可能反映了我们破碎的社会结构——以及当今家庭中代际交流的缺乏——或许,它确实是阿尔茨海默症的生物或化学驱动因素。

所以,让“浸礼宗教徒”“道教徒”和“无神论者”为了晦暗未明的科学争论不休吧,你不如在这个周末给你的母亲、父亲、舅母或老邻居打个电话,唠唠家常。谁知道呢?或许你对抗击阿尔茨海默症所做的贡献,比许多制药公司的高管还要大。(财富中文网)

译者:严匡正

Alzheimer’s disease research has long been beset by a religious war of sorts: “BAPtists” ardently believe that plaques formed by beta-amyloid proteins drive the disease by gumming up and ultimately killing neurons. “TAUists” believe that the real culprits are the neurofibrillary tangles, or twisted tau proteins, that accumulate within neurons. And “ATHIEsts” believe that while both of these factors play a role, anything else may ultimately be to blame for advancing the disease.

As I mentioned in recently article (“Why the Latest Alzheimer’s Drug Has So Many People Confused”), the BAPtists have drawn the greatest number of disciples for a generation or more—on both the academic research and drug development fronts. And amyloid hypothesis backers even have a new biological model to explain how this pathological process might begin—and accelerate. The idea, as writer Laura Beil explains in a wonderfully clear feature in Science News, is called the “clean cycle”:

During normal sleep, the brain actively clears out stray beta-amyloid (also called A-beta), protein remnants that are discarded by neurons themselves. But when sleep is disrupted, the trash removal is stalled: “[T]he brain doesn’t get the chance to mop up all the A-beta that the neurons produce, according to a developing consensus,” Beil writes. “A-beta starts to collect in the small seams between cells of the brain, like litter in the gutter. If A-beta piles up too much, it can accumulate into plaques that are thought to eventually lead to other problems such as inflammation and the buildup of tau, which appears to destroy neurons and lead to Alzheimer’s disease.”

Indeed, thanks to PET scans, we can see that, even in healthy brains, the amount of this stray protein increases dramatically—by as much as 5% in certain brain regions—after only a single night of sleep deprivation. The fact that Alzheimer’s itself disrupts sleep serves only to speed up and amplify this vicious cycle. But there are gaps in the theory, too. One is a chicken-and-egg conundrum, says Beil: “If Alzheimer’s both affects sleep and is affected by it, which comes first?”

Another gap—or at least a confounder—is the fact that amyloid-clearing agents have been tested again and again in investigative clinical trials and have never been shown to halt the disease. As I wrote recently, the recent results from the Phase II trial of BAN2401, an anti-amyloid drug from Biogen and Eisai didn’t exactly break this record. Though patients who received the experimental antibody may have had some improvement in cognition, the outcomes appeared to fall short of what many had hoped for, and even expected.

On top of that comes another weighty question: Call it the seven-ton mystery—or the elephant in the room of Alzheimer’s oddities: Why don’t elephants experience the same kind of brain deterioration with aging?

The brains of Loxodonta africana, or African elephants, are nearly three times larger than their human counterparts—holding as many as 257 billion neuronscompared to our feeble 100 billion or so (though the vast majority of the elephant’s supply reside outside the cerebral cortex). But elephants seem to have extraordinary memory capacity late into life, as Michael Garstang, an emeritus distinguished research professor at the University of Virginia, details in his book Elephant Sense and Sensibility—with herd matriarchs remembering discrete faraway locations visited many decades earlier, for example, and transferring that knowledge to the next generations.

Moreover, to the extent it can be known (It’s hard to ask an elephant what they had for breakfast yesterday), there seems to be little evidence that older elephants suffer from mental decline. So far, in the handful of brains of older elephants that have been examined post-mortem, there’s also no evidence of a buildup of amyloid plaques.

As for the sleep-brain-cleaning thesis, that too runs into a snag with elephants: The creatures, on the whole, sleep very little. (Wild elephants may sleep as little as two hours a day, according to one study, though captive animals tend to sleep longer.) But in any case, if elephants are clearing any amyloid buildup during the course of their zzz’s, there isn’t much time to get it done.

One possible explanation is that elephant brains may have some other biological mechanism for keeping their neurons firing brightly through the decades.

But then, another theory isn’t mechanistic at all—rather, it goes to the heart of elephant life itself: They’re deeply social. The animals congregate for life in tight-knit extended family networks, one generation alongside another. Could that have something to with keeping aged brains humming?

As it turns out, there’s actually a fair amount of research to suggest it might. Several studies in humans have appeared to demonstrate that strong social connections reduce the risk of cognitive impairment in older adults—and that the opposite circumstance (social disengagement) makes mental deterioration worse.

Unfortunately, such evidence might offer one clue as to why Alzheimer’s deaths have been rising in this U.S., increasing 123% between the years 2000 and 2015. In the end, such a sad stat may reflect our frayed social fabric—and the lack intergenerational contact among families today—as much, perhaps, as it does some biological or chemical driver of the disease.

So while the BAPtists and TAUists and ATHIEsts debate the murky science among themselves, give your mom or dad, or aunt, or older neighbor a call this weekend and shoot the breeze. Who knows? You may end up doing more to fight Alzheimer’s than many pharma execs.

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