Lau SF, Wu W, Wong HY, Ouyang L, Qiao Y, Xu J, Lau JH, Wong C, Jiang Y, Holtzman DM, Fu AK, Ip NY. The VCAM1-ApoE pathway directs microglial chemotaxis and alleviates Alzheimer's disease pathology. Nat Aging. 2023 Oct;3(10):1219-1236. Epub 2023 Sep 21 PubMed.

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  1. In this paper, Dr. Ip and colleagues extended their prior research on the role of interleukin-33 (IL-33) in microglial Aβ clearance. Their previous work had suggested that after injection in APP/PS1 mice IL-33 facilitates microglial Aβ clearance by initially inducing Aβ chemotaxis followed by Aβ phagocytosis (Lau et al., 2020). However, the precise pathway regulating this microglial response was unclear.

    In this study, the researchers conducted a series of experiments to uncover these mechanisms. Through both bulk and single-cell transcriptomic analyses, they validated that, at the transcriptomic level, microglia transition from a homeostatic state to a chemotactic state, and subsequently to an Aβ-phagocytic state following IL-33 injection, consistent with their earlier findings. Furthermore, they identified a crucial role for VCAM1 in enabling microglia to acquire these chemotactic states after IL-33 injection. This was confirmed through experiments involving microglia-specific VCAM1 conditional knockout mice, which displayed an inability to respond to Aβ after IL-33 injection, among other supporting evidence. They also demonstrated that the injection of recombinant ApoE, not lipidated ApoE, could attract VCAM1+ microglia following IL-33 injection, and that the administration of an ApoE neutralizing antibody disrupted the IL-33-mediated migration of VCAM1+ microglia to Aβ plaques. These findings suggest that VCAM1+ microglia migrate toward Aβ plaques by sensing non-lipidated ApoE within these plaques. Finally, in humans, the team observed elevated soluble VCAM1 levels in both plasma and CSF among AD patients compared to control subjects. Additionally, CSF soluble VCAM1 levels showed a negative correlation with the presence of microglia surrounding Aβ plaques.

    This paper presents a compelling connection between ApoE and VCAM1 in the IL-33-mediated microglial response to Aβ plaques. It also opens the door to several intriguing questions that merit further investigation. I think one critical area for exploration is the necessity for additional evidence elucidating how non-lipidated ApoE binds to VCAM1 and why lipidation of ApoE disrupts this interaction. It is also worth considering whether ApoE aggregation plays a role in this interaction, given that ApoE co-deposited with Aβ plaques is typically insoluble. Clarifying this distinction is essential for defining ApoE as a ligand for VCAM1. Another question is whether the ApoE-VCAM1 axis regulates microglial responses exclusively following IL-33 injection or if it represents a general mechanism by which microglia sense and respond to Aβ plaques. Drawing from Kim et al.'s work , it is worth noting that treatment with the ApoE neutralizing antibody (HJ6.3) appeared to significantly enhance microglial activity and reduce Aβ plaque load, contrasting the observations in this paper, where the administration of the same ApoE antibody reduced the microglial response to Aβ and abolished the IL-33-induced Aβ clearance (Kim et al., 2012). This suggests that the presence of IL-33 might alter ApoE-related microglial functions.

    Overall, this outstanding paper by Dr. Ip and colleagues, along with the further questions it prompts, has the potential to significantly advance our understanding of ApoE and microglial biology in response to amyloid pathology.

    References:

    Lau SF, Chen C, Fu WY, Qu JY, Cheung TH, Fu AK, Ip NY. IL-33-PU.1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in Alzheimer's Disease. Cell Rep. 2020 Apr 21;31(3):107530. PubMed.

    Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB, Stewart FR, Basak JM, Holtzman DM. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis. J Exp Med. 2012 Nov 19;209(12):2149-56. PubMed.

    View all comments by Na Zhao

  2. This looks like an interesting new role for VCAM1 in facilitating microglia migration to and phagocytosis of amyloid plaques. Although VCAM1 is well known to be involved in the interactions of monocytes and other immune cells with endothelial cells, this proposed function in microglia would be qualitatively different. The connection to ApoE is also interesting, but at present it is not clear whether, and if so how, VCAM1 directly detects ApoE. It will be of substantial interest to explore this aspect of the findings further and determine whether there are differences with respect to APOE3 and APOE4 alleles.

    View all comments by Christopher Glass

  3. The APOE-TREM2 interaction is well established but APOE-VCAM1 may be an important co-stimulatory pathway for microglial recruitment to amyloid plaques. Indeed, AD patients with TREM2 R47H mutations still show recruitment of microglial to the amyloid plaque region and their hyperactivation (Korvatska et al., 2015; Sayed et al., 2021), although transplanted human TREM2 R47H iPSC-derived microglia show reduced plaque reactivity in the 5xFAD mouse model (Claes et al., 2021). These conflicting results may be due to the difference in the induction of the alternative pathway for the recruitment of microglia to the plaque region. Targeting VCAM1 may be an attractive alternative approach because treatment of AD cases with anti-TREM2 antibody was recently reported to induce ARIA (Aug 2023 news /news/conference-coverage/aria-inflammatory-reaction-vascular-amyloid).

    References:

    Korvatska O, Leverenz JB, Jayadev S, McMillan P, Kurtz I, Guo X, Rumbaugh M, Matsushita M, Girirajan S, Dorschner MO, Kiianitsa K, Yu CE, Brkanac Z, Garden GA, Raskind WH, Bird TD. R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study. JAMA Neurol. 2015 Aug;72(8):920-7. PubMed.

    Sayed FA, Kodama L, Fan L, Carling GK, Udeochu JC, Le D, Li Q, Zhou L, Wong MY, Horowitz R, Ye P, Mathys H, Wang M, Niu X, Mazutis L, Jiang X, Wang X, Gao F, Brendel M, Telpoukhovskaia M, Tracy TE, Frost G, Zhou Y, Li Y, Qiu Y, Cheng Z, Yu G, Hardy J, Coppola G, Wang F, DeTure MA, Zhang B, Xie L, Trajnowski JQ, Lee VM, Gong S, Sinha SC, Dickson DW, Luo W, Gan L. AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation. Sci Transl Med. 2021 Dec;13(622):eabe3947. PubMed.

    Claes C, Danhash EP, Hasselmann J, Chadarevian JP, Shabestari SK, England WE, Lim TE, Hidalgo JL, Spitale RC, Davtyan H, Blurton-Jones M. Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease. Mol Neurodegener. 2021 Jul 23;16(1):50. PubMed.

    View all comments by Tsuneya Ikezu

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