De Schepper S, Ge JZ, Crowley G, Ferreira LS, Garceau D, Toomey CE, Sokolova D, Rueda-Carrasco J, Shin SH, Kim JS, Childs T, Lashley T, Burden JJ, Sasner M, Sala Frigerio C, Jung S, Hong S. Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease. Nat Neurosci. 2023 Mar;26(3):406-415. Epub 2023 Feb 6 PubMed.

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  1. This very exciting paper opens new perspectives on how to modulate microglia pathological activity, such as synapse engulfment, that probably contributes to cognitive decline in AD. The identified crosstalk between microglia and perivascular macrophages through SPP1 in early AD models is novel and offers new possible interventions to modulate microglia activity.

    It is interesting to see that perivascular macrophages—which are guardians of tissue permeability and, here, sit at the interface between the brain and the circulation—control microglia activity. New questions raised include how to prevent SPP1 expression by such perivascular macrophages, and how to find additional molecular pathways that regulate microglia and perivascular macrophage crosstalk.

    View all comments by Florent Ginhoux

  2. This is exciting new study by Soyon Hong‘s group from UK DRI@UCL provides evidence for a key role of border-associated macrophages in modulating microglia function. The paper also demonstrates the power of new binary Cre transgenic mouse models in differentiating the functions of different macrophage populations within the CNS.

    It would be exciting to see what role the crosstalk between perivascular macrophages and microglia via osteopontin plays in neuroinflammatory diseases such as multiple sclerosis, where we identified osteopontin-expressing microglia.

    View all comments by Josef Priller

  3. I found this paper very exciting! In a recent study, we found that higher baseline levels of SPP1 (osteopontin) in cerebrospinal fluid correlated with worse accumulation of tau pathology and cognitive deterioration over time in individuals with preclinical/prodromal AD. This was in contrast to the other studied DAM-associated markers (like sTREM2, AXL, MERTK, GAS6, LPL, CST7, and CSF1), which were instead associated with a more beneficial outcome. I think the current paper by De Schepper et al. helps us understand why SPP-1 has detrimental effects in AD. Further work focusing in the effects of SPP1 on tau pathology in AD might be warranted.

    References:

    Pereira JB, Janelidze S, Strandberg O, Whelan CD, Zetterberg H, Blennow K, Palmqvist S, Stomrud E, Mattsson-Carlgren N, Hansson O. Microglial activation protects against accumulation of tau aggregates in nondemented individuals with underlying Alzheimer’s disease patholog. Nat Aging 2, 1138–1144 (2022)

    View all comments by Oskar Hansson

  4. This is a nice study by De Schepper et al. that highlights the importance of the brain perivascular immune niche in modulating microglial function in the APPNL-F AD mouse model. The authors demonstrate that the immune protein SPP1 is produced predominantly by perivascular macrophages and works as a probable soluble factor to promote microglia phagocytosis of synapses, particularly in response to Aβ oligomers. SPP1 has been shown to be elevated in AD CSF, and PVMs may therefore be one source of this CSF protein.

    A number of intriguing questions are raised by the results of this study. What is special about the perivascular space in the hippocampus compared to other brain regions? Might PVM-mediated secretion of SPP1 be one mechanism by which peripheral inflammation or cerebral amyloid angiopathy influence synaptic health? Is PVM-mediated secretion of SPP1 also important in the microglial response to Aβ plaques?

    One potential therapeutic implication of these results is that targeted reduction of SPP1 in brain may help to promote beneficial TREM2-mediated phagocytosis of Aβ by microglia while minimizing the risk of “collateral” synaptic damage from microglial activation, particularly given the finding that knockout of SPP1 does not appear to impair microglial phagocytic competence, at least in vitro.  It will be exciting to see how these findings might translate into new therapeutic approaches for synapse preservation in AD.

    View all comments by Erik Johnson

  5. This very interesting work suggests a central role of SPP1/osteopontin)in Aβ aggregation along the vasculature.

    Interestingly, in patients with Dutch-type cerebral amyloid angiopathy (D-CAA), an early onset hereditary form of CAA due to the APP E693Q mutation, we described an accumulation of osteopontin and TGFβ signaling factor phospho-SMAD2/3 in CAA vessels, as well as the association of col1 protein, a fibrotic protein with vascular amyloid load (Grand Moursel et al., 2019). Upregulation in extracellular matrix pathways in relation to an increase in the Transforming Growth Factor beta (TGFβ) signaling pathway was identified as well in our transcriptomic study in human postmortem D-CAA brain (Grand Moursel et al., 2018).

    In D-CAA, accelerated generation or stability of toxic oAβ species has been suggested, although never proven, in patients. Considering De Schepper et al.’s finding that perivascular macrophages act as a major source of osteopontin upon oAβ challenge, toxic oAβ species in D-CAA could be an early trigger of vascular amyloid aggregation resulting in severe CAA. It would be interesting to further investigate if modulation of osteopontin in perivascular macrophages could reduce the CAA phenotype.

    References:

    Grand Moursel L, van der Graaf LM, Bulk M, van Roon-Mom WM, van der Weerd L. Osteopontin and phospho-SMAD2/3 are associated with calcification of vessels in D-CAA, an hereditary cerebral amyloid angiopathy. Brain Pathol. 2019 Mar 13; PubMed.

    Grand Moursel L, van Roon-Mom WM, Kiełbasa SM, Mei H, Buermans HP, van der Graaf LM, Hettne KM, de Meijer EJ, van Duinen SG, Laros JF, van Buchem MA, 't Hoen PA, van der Maarel SM, van der Weerd L. Brain Transcriptomic Analysis of Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch Type. Front Aging Neurosci. 2018;10:102. Epub 2018 Apr 13 PubMed.

    View all comments by Laure Grand Moursel

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