Team Drieu

The perivascular space unit in the healthy and diseased brain

Neurons are the cells responsible for brain functions, and inevitably produce metabolic waste that can be toxic. However, the brain, unlike other organs, does not contain lymphatic vessels necessary for the proper clearance of waste debris. The brain therefore had to adapt anatomically to this constraint in order to free itself from its waste and maintain its normal functions.

It has been demonstrated that cerebrospinal fluid (CSF) can penetrate the brain parenchyma and then exit the brain carrying the accumulated waste. We recently showed that resident macrophages in the CSF surrounding blood vessels, so-called perivascular macrophages, can regulate the movement of blood vessels that are essential for cerebrospinal fluid flow into the brain. Dysfunction of these macrophages leads to dysfunction of the perivascular space and consequently to poor clearance of waste. Our team is interested in how to regulate this perivascular space as well as the cells composing it, with the aim of maintaining normal brain functions.
    Figure :

 

The cerebrospinal fluid in the perivascular space can penetrate the brain parenchyma, mix with the interstitial fluid and exit the brain accompanied by waste debris, which will ultimately reach the dura mater and meningeal lymphatic vessels to be drained into deep cervical lymph nodes. Parenchymal border macrophages (PBMs), representing both perivascular and leptomeningeal macrophage populations, regulate vasomotion, the main driver of cerebrospinal fluid flow.

 

5 Main Publications :

Drieu A, Du S, Storck SE, Rustenhoven J, Papadopoulos Z, Dykstra T, Zhong F, Kim K, Blackburn S, Mamuladze T, Harari O, Karch CM, Bateman RJ, Perrin R, Farlow M, Chhatwal J, Hu S, Randolph GJ, Smirnov I, Kipnis J. Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid. Nature. 2022 Nov;611(7936):585-593. doi: 10.1038/s41586-022-05397-3. Epub 2022 Nov 9. PubMed PMID: 36352225; PubMed Central PMCID: PMC9899827.

 

Jiang-Xie LF, Drieu A, Kipnis J. Waste clearance shapes aging brain health. Neuron. 2024 Oct 8;. doi: 10.1016/j.neuron.2024.09.017. [Epub ahead of print] Review. PubMed PMID: 39395409.

 

Jiang-Xie LF, Drieu A, Bhasiin K, Quintero D, Smirnov I, Kipnis J. Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance. Nature. 2024 Mar;627(8002):157-164. doi: 10.1038/s41586-024-07108-6. Epub 2024 Feb 28. PubMed PMID: 38418877.

 

Smyth LCD, Xu D, Okar SV, Dykstra T, Rustenhoven J, Papadopoulos Z, Bhasiin K, Kim MW, Drieu A, Mamuladze T, Blackburn S, Gu X, Gaitán MI, Nair G, Storck SE, Du S, White MA, Bayguinov P, Smirnov I, Dikranian K, Reich DS, Kipnis J. Identification of direct connections between the dura and the brain. Nature. 2024 Mar;627(8002):165-173. doi: 10.1038/s41586-023-06993-7. Epub 2024 Feb 7. PubMed PMID: 38326613; PubMed Central PMCID: PMC11254388.

 

Rustenhoven J, Drieu A, Mamuladze T, de Lima KA, Dykstra T, Wall M, Papadopoulos Z, Kanamori M, Salvador AF, Baker W, Lemieux M, Da Mesquita S, Cugurra A, Fitzpatrick J, Sviben S, Kossina R, Bayguinov P, Townsend RR, Zhang Q, Erdmann-Gilmore P, Smirnov I, Lopes MB, Herz J, Kipnis J. Functional characterization of the dural sinuses as a neuroimmune interface. Cell. 2021 Feb 18;184(4):1000-1016.e27. doi: 10.1016/j.cell.2020.12.040. Epub 2021 Jan 27. PubMed PMID: 33508229; PubMed Central PMCID: PMC8487654.

  

Keywords

Brain, meninges, perivascular spaces, immune system, cerebrospinal fluid

Main techniques/approaches:

We will first study the origin/development of perivascular spaces in vivo and using spatial transcriptomics. We will study the interactions between perivascular macrophages and other cells residing in the perivascular space using various genetic mouse models and in vitro approaches. Finally, we will study the dysfunction of perivascular spaces in vivo and with single cell RNA sequencing.

Main Funding: