Peripheral cancer attenuates amyloid pathology in Alzheimer’s disease via cystatin-c activation of TREM2, 2026, Li et al.

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Peripheral cancer attenuates amyloid pathology in Alzheimer’s disease via cystatin-c activation of TREM2

Spoiler: Authors

Xinyan Li; Xiaomei Tang; Jinyu Zeng; Limin Duan; Zhenye Hou; Lanfang Li; Yiqing Guo; Changdong Chai; Jiahao Liu; Ya Wang; Ling-Qiang Zhu; Hao Li; Tongmei Zhang; Yue Wang; Aodi He; Youming Lu

Alzheimers disease (AD) and cancer are among the most devastating diseases worldwide. Epidemiological data indicate that the incidence of AD significantly decreases in patients with a history of cancer. However, whether and how peripheral cancer may affect AD progression is yet to be studied.

Here, we find that peripheral cancer inhibits amyloid pathology and rescues cognition via secretion of cystatin-c (Cyst-C), which binds amyloid oligomers and activates triggering receptor expressed on myeloid cells 2 (TREM2) in microglia, enabling microglia to degrade the pre-existing amyloid plaques in AD mice. These effects of Cyst-C are abolished by a cell-type-specific deletion (Cx3cr1TREM2−/−) or mutation of TREM2 (TREM2R47H) or Cyst-C (Cyst-CL68Q) in microglia.

Together, these findings provide significant conceptual advances into cancer neuroscience and establish therapeutic avenues that are distinct from the present amyloid-lowering strategies, aiming at degrading the existing amyloid plaques for precision-targeted AD therapy.

HIGHLIGHTS
• Fight Alzheimers disease with peripheral cancers via Cyst-C secretion

• Tumor-derived Cyst-C attenuates amyloid pathology of Alzheimers disease

• Human Cyst-C binds amyloid oligomers and activates TREM2

• Tumor-derived Cyst-C degrades pre-existing amyloid plaques via TREM2

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Nature News Cancer might protect against Alzheimer’s — this protein helps explain why

For decades, researchers have noted that cancer and Alzheimer’s disease are rarely found in the same person, fuelling speculation that one condition might offer some degree of protection from the other.

Now, a study in mice provides a possible molecular solution to the medical mystery: a protein produced by cancer cells seems to infiltrate the brain, where it helps to break apart clumps of misfolded proteins that are often associated with Alzheimer’s disease. The study, which was 15 years in the making […] could help researchers to design drugs to treat Alzheimer’s disease.

Weaver has been interested in that puzzle ever since he began his medical training, when a senior pathologist made an offhand comment: “If you see someone with Alzheimer’s disease, they’ve never had cancer.” The remark stuck with Weaver over the years as he diagnosed thousands of people with Alzheimer’s disease. “I can’t remember a single one that has had cancer,” he says.

Epidemiological data do not draw such a clear divide, but a 2020 meta-analysis of data from more than 9.6 million people found that cancer diagnosis was associated with an 11% decreased incidence of Alzheimer’s disease. It has been a difficult relationship to unpick: researchers must control for a variety of external factors. For example, people might die of cancer before they are old enough to develop symptoms of Alzheimer’s disease, and some cancer treatments can cause cognitive difficulties, which could obscure an Alzheimer’s diagnosis.

Over the years, however, the data converged enough to convince Youming Lu, a neurologist at Huazhong University of Science and Technology in Wuhan, China, to take a closer look at the biology underlying this trend.

Further experiments in mice showed that cystatin C binds to the molecules that make up the hallmark brain plaques of Alzheimer’s disease. This interaction activates a signalling protein, called TREM2, that is found on certain immune cells that patrol the brain.

Those immune cells then degrade the plaques. In Lu’s mice, this plaque degradation was linked to an improved performance on cognitive tests.

So far, early clinical trials of molecules that activate TREM2 have met with mixed results, he says. But that doesn’t mean it’s a dead end. “It’s going to take a cocktail of drugs to treat Alzheimer’s disease,” he says. “There’s not going to be a single magic bullet.”

 

[Hutan]

(cross post with the above post where the article excerpts say something similar about the epidemiology)

Epidemiological data indicate that the incidence of AD significantly decreases in patients with a history of cancer.

I think it's an interesting puzzle to think about how this could be true without the cancer secreting something that reduces AD pathology.

The incidence of AD is lower and diagnosed later in highly educated people - it's supposed to be due to the cognitive reserve. If you have a mind that was capable of, for example, writing complicated legal documents before you retired, you can probably lose more brain cells before you have trouble with the shopping list. You might also care more about hiding your cognitive dysfunction.

Highly educated people are likely to have all sorts of advantages, including more stable and higher quality medical care. So, their cancers are more likely to be diagnosed early and they are more likely to survive them. Poorly educated people are less likely to get their cancers diagnosed early or at all and are more likely to die of them.

I think that would tend to skew the people in the [history of diagnosed cancer but still alive] group towards the highly educated people, the people who are less likely to get a diagnosis of AD at a given age. I'd want to see those epidemiological studies controlling for things like education and socioeconomic class before I'd believe they are evidence that cancer protects against AD.


Also, I'm not sure if it has been proven that the amyloid plaques that the cystatin-c acts against are a cause of AD rather than a result? Still, it's an interesting idea that there might be a benefit from a cancer and that they might have found something that degrades amyloid plaques.