Da Mesquita S, Papadopoulos Z, Dykstra T, Brase L, Farias FG, Wall M, Jiang H, Kodira CD, de Lima KA, Herz J, Louveau A, Goldman DH, Salvador AF, Onengut-Gumuscu S, Farber E, Dabhi N, Kennedy T, Milam MG, Baker W, Smirnov I, Rich SS, Dominantly Inherited Alzheimer Network, Benitez BA, Karch CM, Perrin RJ, Farlow M, Chhatwal JP, Holtzman DM, Cruchaga C, Harari O, Kipnis J. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature. 2021 May;593(7858):255-260. Epub 2021 Apr 28 PubMed.

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  1. This paper adds to the important literature from the Kipnis lab that establishes the brain’s meningeal lymphatics as a critical interface between the nervous and immune systems. Using photoablation protocols to eliminate the lymphatic vasculature of the dorsal meninges in mice, Da Mesquita and colleagues demonstrate that this vasculature is important for the ability of anti-Aβ antibodies to reduce plaque burden in amyloidogenic mouse models of Alzheimer’s disease (AD). Conversely, the authors show that enhancing lymphatic vascular integrity through expression of vascular endothelial growth factor C potentiates the Aβ plaque-clearing efficacy of these antibodies, human versions of which are currently in clinical trials or awaiting approval as AD therapeutics.

    Using transcriptomic profiling, the authors identify genetic similarities between microglia from 5xFAD brains with ablated meningeal lymphatics and human microglia from AD patients, suggesting a potential role of compromised brain lymphatics in human AD. They also note that AD genetic variants that are expressed by lymphatic endothelial cells are associated with altered microglial gene expression in human cortex. This strengthens the connection between meningeal lymphatic impairment and aberrant microglial activation in AD, though the mechanism behind this connection requires further study.

    CNS lymphatics have been overlooked in health and disease until recently, and there is little known about how dysfunction in meningeal lymphatic drainage might affect the outcome of immunotherapy in AD. This study is therefore topical, as it provides an alternative perspective with respect to results from current and past immunotherapies for AD.  

    View all comments by Youtong Huang

  2. I think this is very interesting work, and the authors deserve credit for looking at parallels between human disease and the mouse models used. Clinically, the work may be highly relevant since the data imply that meningeal lymphatics are important for drug delivery. This makes a lot of sense to me, as this type of drug delivery problem is a frequent issue in many settings, for instance in cancer. It is likely even more relevant because of the insulating nature of the blood-brain barrier.

    Overall, the meninges and brain lymphatics are increasingly getting attention, and I believe rightly so. They provide important routes (or barriers) to the brain, especially for wandering cells, such as immune cells.

    View all comments by Matthias Nahrendorf

  3. This paper is very valuable in connecting the neuroimmunology of the meningeal lymphaticswith microglia—the innate immune system for the brain, especially in the context of immunization against Aβ.

    It is interesting that in mice with impaired meningeal lymphatic drainage the administration of the mAb158 antibody resulted in less mAb158 co-localizing with the parenchymal plaques, but no effect on the amount of mAb158 co-localizing with vascular Aβ. This suggests that meningeal lymphatic biology is directly connected to the innate immune system of the brain, but more investigations into its connections with the intramural periarterial drainage pathways for the clearance of interstitial fluid are required.

    View all comments by Roxana Carare

  4. In this interesting paper, the authors demonstrate the importance of an intact meningeal lymphatic system for successful passive Aβ immunotherapy. Furthermore, gene signature data, from both a mouse AD model and AD patients, suggest a link between meningeal lymphatic dysfunction and microglia activation.

    The authors provide convincing data that therapeutic antibodies directed toward Aβ are less efficient in entering brain parenchyma and consequently, they largely fail to clear Aβ plaques following induced disruption of meningeal lymphatic vessels. They demonstrate that by restoring lymphatic vessel integrity by viral VEGF-C expression, antibody-mediated Aβ clearance was improved.

    As there was significantly less co-localization of the administrated anti-Aβ antibody with brain parenchymal Aβ aggregates, it is likely that the circulation between cerebral spinal fluid, glymphatic flow, and interstitial fluid has been compromised by the loss of lymphatic vasculature, thereby lowering the brain exposure through this specific route. A more direct pathway into the brain is to cross the blood-brain barrier (BBB). Different technologies are now being developed to transport biotherapeutics over the BBB so it would be interesting to investigate if a BBB transport approach is affected by meningeal lymphatic dysfunction. This would help to understand if the lower clearance of Aβ plaques with an anti-Aβ antibody in mice with loss of lymphatic vasculature is due to less drainage capacity or a direct reduction in brain exposure of the antibody.

    The development of a gene signature of early meningeal lymphatic dysfunction, potentially aligned with microglial activation and angiopathy, has the potential to allow patient stratification for immunotherapies of AD. Enhancement of meningeal lymphatic function combined with immunotherapy might in the future lead to better clinical outcomes.

    View all comments by Lars Lannfelt

  5. This interesting paper convincingly shows that elimination of meningeal lymphatics by photoablation increases the amyloid plaque load in the cortices and thalami of 5xFAD mice. However, the claim that “Compromised meningeal lymphatic function in 5xFAD mice limits brain Aβ clearance by chimeric mAducanumab” (Fig. 1 heading) needs to be interpreted with caution. The claim is based on Fig. 1d showing significantly larger amyloid plaque coverage per brain section in mAb-treated mice with photoablation than in treated mice with intact menigeal lymphatics in a paired comparison.

    This is only a partial view of the big picture. The study had a typical 2 x 2 design and should be analyzed with two-way ANOVA. This would have shown a significant main effect of the photoablation, as well as a significant effect of the mAb treatment. However, there is no interaction between these two factors, which would support the given claim.

    In fact, Fig. 1c, presenting the amyloid plaque number per mm2 with all four study groups, shows a similar a mAb treatment effect in mice with and without photoablation. Fig. 1d would most likely look the same had all the four groups been shown.

    Further, the analysis of dystrophic neurites stained by LAMP1 (Fig 1e) might actually show a significant lesion by mAb treatment interaction but to the opposite direction as claimed. The treatment effect is minimal in mice with intact meningeal lymphatics (due to overall small number of these dystrophies) but highly significant in mice with ablated lymphatics. Thus, the correct interpretation of the data is that photoablation of meningeal lymphatics results in increased brain amyloid load but does not mitigate the Aβ clearance by systemic administration of mAducanumab.

    Interestingly, the situation is somewhat different when the antibody (this time mAb158) is administered directly to CSF. As seen in Extended Fig. 5e and g, the number of plaques per mm2 and plaque coverage per brain section are reduced by the mAb treatment in mice with intact meningeal lymphatics, but not in mice with photoablation. It is a pity that this second study was carried out with a different mAb than the first one, leaving open the question whether the difference is due to the route of administration or the antibody itself. The different outcomes of meningeal lymphatic ablation on systemic versus local anti-Aβ mAb warrant further studies.

    View all comments by Heikki Tanila

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