"Nature": A major breakthrough in Alzheimer's disease immunotherapy!

How far is Alzheimer's disease (AD) from us? It’s not far at all.
As long as they live long enough, everyone can’t avoid it.
However, no specific medicine for AD has been approved yet.

Singularity Cake is well aware of the difficulties of new AD drug research and development.
Take the beta amyloid (Aβ) antibody aducanumab, which is undergoing drug review in the United States, the European Union, and Japan, the current clinical trial results are still not satisfactory [1].

Recently, a research team led by Jonathan Kipnis and Sandro Da Mesquita of the University of Virginia Neuroscience published important research results in the top journal Nature, which ushered in a turning point for AD immunotherapy targeting Aβ.

They found that disrupting the meningeal lymphatic drainage function would aggravate the pathological response and cognitive impairment of AD mice; and enhancing the meningeal lymphatic drainage combined with immunotherapy targeting Aβ can significantly improve the pathological and cognitive symptoms of mice.

Their research shows that "keep the brain's'transportation channels' unblocked" is of great significance for the treatment of all brain diseases including AD [2].

The screenshots of this research paper turned around, and when the willows were bright, the treatment of AD finally saw the light of day.

As early as 2015, Jonathan Kipnis published a paper in Nature for the first time, describing the presence of lymphatic ducts in the dura mater, which drains macromolecules from the brain to the deep cervical lymph nodes.
This discovery overturned the textbooks for decades.
The old concept of "no lymphatic vessels in the brain" [3].

Later in 2019, Jonathan Kipnis et al.
once again described the structure and drainage function of meningeal lymphatic vessels in "Nature", and pointed out that destroying meningeal lymphatic vessels would accelerate the deposition of Aβ and promote the progression of AD [4].

Aβ has always been considered to be a hallmark of AD’s pathological features and a key factor in the onset of disease.
A monoclonal antibody targeting Aβ to promote amyloid clearance is a promising treatment strategy.

Faced with the inconsistent results of clinical trials of aducanumab, Jonathan Kipnis and others wanted to know whether changing the drainage of meningeal lymphatic vessels would affect the immunotherapy effect of AD.

So there is this third study published in Nature.

The researchers first found that AD model mice (5xFAD mice) gradually decreased the function of meningeal lymphatic vessels with age, and the deposition of Aβ along the meningeal lymphatic vessels gradually increased.

When the mouse version of aducanumab (mAdu) is used to treat AD mice, it can improve the pathology and cognitive function of Aβ in mice.

In order to further study the influence of the changes in meningeal lymphatic vessels on Aβ immunotherapy, the researchers first used the photosensitizer Visudal combined with laser therapy (Vis/photo) to construct a mouse meningeal lymphatic ablation model; when the simple injection of Visudal ( Vis), the structure and function of the lymphatic vessels in the meninges of mice are not affected.

Then they divided the mice into 4 groups, namely Vis/photo group and Vis group receiving mAdu treatment, and Vis/photo group and Vis group receiving mIgG control treatment.

What is interesting is that in mice without immunotherapy and ablation of meningeal lymphatic vessels, Aβ deposition was significantly increased than in other mice, and cognitive and memory functions were also significantly impaired.

And among all the mice that received mAdu treatment, the meningeal lymphatic ablation group mice also had heavier pathology and poorer cognitive function than the normal AD group mice.

The ablation of meningeal lymphatic vessels (Vis/photo) accelerated the deposition of Aβ in mice; at the same time, cognitive function and memory function were also significantly reduced.
In order to explain the decrease in the efficacy of Aβ immunotherapy in mice in the meningeal lymphatic ablation group, the researchers put mAdu It was directly injected into the cerebrospinal fluid of mice, and it was found that the binding of mAdu and Aβ in the brain parenchyma in mice with missing meningeal lymphatic vessels was significantly reduced.

From this, the researchers inferred that: due to damage to the lymphatic vessels, the amount of drugs entering the brain tissue from the cerebrospinal fluid is reduced, which affects the targeting of mAdu to Aβ clearance, thereby reducing the curative effect of mAdu.

More interestingly, when they injected mouse-derived vascular endothelial growth factor-C to enhance the function of meningeal lymphatic vessels, and gave mAdu treatment at the same time, they found that the amyloid pathology and cognitive function of the mice had actually been reversed! mVEGF-C treatment enhances the function of the meningeal lymphatic vessels in mice and significantly reduces Aβ in the mouse brain.
The research results published in Nature by Jonathan and others in 15 years have shown that the meningeal lymphatic vessels drain the brain's macromolecular substances into the neck Deep lymph nodes.

In this way, intact meningeal lymphatic vessels are similar to the "pipes" in the brain, and Aβ monoclonal antibodies are similar to "detergents.
"
In the process of completing the removal of Aβ, the meningeal lymphatic vessels are required to transport the "detergent" to the vicinity of the "trash".

Therefore, in the process of clearing the brain's "junk", if immune preparations want to play a better effect, the strong meningeal lymphatic transport capacity is particularly important.

In addition, the researchers found another important neuroinflammation pathological manifestation of AD during the observation of the pathological process of amyloid in mice: the ablation of meningeal lymphatic vessels can cause abnormal activation of microglia in AD mice.

As a "cleaner" in the brain, microglia play an important role in the pathogenesis and progression of AD [5].
In order to explore the relationship between microglia and AD, researchers used single-cell sequencing to analyze AD models.
The gene expression patterns of microglia in mice in different states of meningeal lymphatic vessels.

They found that meningeal lymphatic ablation caused the microglia to shift from an equilibrium state to an activated state and express disease-associated microglia (DAM) genes.

Meningeal lymphatic ablation causes the microglia to switch from steady state to activated and express disease-associated microglia (DAM) genes.
To further explore the underlying mechanism of this phenomenon, the researchers performed microglia in mice and humans.
Integrated transcription analysis found that more than half of the microglia in normal people are in a balanced state; AD patients are rich in activated microglia; most of the microglia in ultra-early AD patients are in an alternately activated state.

In AD mice with ablation of meningeal lymphatic vessels, the proportion of balanced microglia decreased significantly, and the activated state increased significantly.

In addition, there is a significant overlap between the transcription patterns of activated microglia in AD mice with meningeal lymphatic vessel dysfunction and AD patients.

There is a significant overlap between the transcription profiles of activated microglia in AD mice with meningeal lymphatic vessel dysfunction and AD patients (1: equilibrium state; 2: activated state (DAM); 3.
alternately activated state; 4, 5: Expression of more activated genes) Through the above analysis, the dysfunction of meningeal lymphatic vessels seems to be consistent with the activation state of microglia.

The researchers pointed out that in the future, by analyzing the genetic status of the microglia of AD patients, inferring the function of meningeal lymphatic vessels, and stratifying the patients for immunotherapy, the function of meningeal lymphatic vessels can be improved as early as possible in order to perform better immunotherapy.
effect.

In general, this article is a continuation of their previous research results on meningeal lymphatic vessels.
If the meningeal lymphatic function can be enhanced in the early stage and combined with immunotherapy, the function of the meningeal lymphatic vessels may be brought into play in AD patients.
Come unexpected clinical results.

Here, Qidian Cake and everyone look forward to the emergence of better curative drugs.

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1038/s41582-020-00435-y Responsible EditorBioTalker