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Nature Aging: Glial Cells Identify and Clear Aβ through the VCAM1-ApoE Pathway and Alleviating Alzheimer's Disease Pathology

A recent study published in the journal Nature Aging by Professor Yee Yvonne's team at the Hong Kong University of Nature Aging and Technology reveals a fascinating discovery. They found that IL-33 induces the expression of VCAM1 in microglial cells, promoting chemotaxis of these cells towards β-amyloid (Aβ) plaques and leading to the clearance of Aβ.

Figure from Nature Aging, 2023, doi:10.1038/s43587-023-00491-1.

The research unveils the role of IL-33 in inducing VCAM1 expression in microglial cells, thereby facilitating the chemotaxis of these cells towards Aβ plaques associated with ApoE and subsequent Aβ clearance. Functional screening also demonstrated that VCAM1 guides microglial cells' chemotaxis by sensing Aβ plaque-associated ApoE. Furthermore, disrupting the VCAM1-ApoE interaction impairs microglial cells' ability to clear Aβ, leading to a decline in their Aβ clearance capacity. Additionally, the study team found that higher levels of soluble VCAM1 in cerebrospinal fluid are correlated with impaired microglial cell chemotaxis toward Aβ in Alzheimer's disease patients.

These findings reveal an unexpected role for Aβ plaque-associated ApoE as a chemical inducer guiding microglial cell migration. The research suggests that the interaction between microglial cell receptors and Aβ plaque-associated factors controls the chemotactic behavior of microglial cells, leading to Aβ clearance. These findings also hint at the potential to improve Alzheimer's disease pathology by enhancing microglial cell function dependent on the VCAM1-ApoE pathway.

In the clearance process of damage-associated molecular patterns (DAMP), microglial cells change their receptor expression profile as they transition between functional states. In response to Aβ aggregation, microglial cells adopt a phagocytic cell phenotype and express genes associated with disease-related microglial cells (DAM), such as increased expression of receptor receptors (Axl and Trem2).

In their previous studies, Yee Yvonne's team showed that Interleukin-33 (IL-33) precisely enhances the clearance of Aβ by microglial cells. Through two-photon live imaging and flow cytometry analysis, the research team observed that in APP/PS1 mice (a transgenic mouse model of amyloidosis), microglial cells first exhibit Aβ chemotaxis (3-12 hours later), followed by Aβ phagocytosis (15-24 hours later).

In this latest study, Yee Yvonne's team further explored how the treatment with IL-33 in APP/PS1 mice regulates the interactions between receptor receptors and their ligands and how this impacts the clearance of DAMP by microglial cells. Addressing these knowledge gaps will provide valuable insights into the role of receptor-ligand interactions in microglial cell DAMP clearance in Alzheimer's disease.

The research demonstrates that the induction of the chemokine protein VCAM1 in microglial cells enhances their interaction with the homologous ligand ApoE, thereby driving Aβ chemotaxis and subsequent Aβ clearance. Single-cell transcriptomics and lineage development analysis show that in APP/PS1 mice treated with IL-33, microglial cells adopt a chemotactic state before transitioning into an Aβ phagocytic state. In this state, they exhibit Aβ-directed migration. Furthermore, functional screening revealed that VCAM1 regulates the chemotaxis of microglial cells towards Aβ plaques by sensing ApoE in the Aβ plaques. Blocking the VCAM1-ApoE interaction after IL-33 treatment inhibits the Aβ chemotaxis of microglial cells and their subsequent differentiation into phagocytic microglial cells.

Moreover, in the brains of Alzheimer's disease patients, VCAM1 signaling is impaired and associated with impaired microglial cell migration towards Aβ plaques.

Figure from Nature Aging, 2023, doi:10.1038/s43587-023-00491-1.

In conclusion, these findings underscore the importance of the VCAM1-ApoE pathway in promoting microglial cell chemotaxis towards Aβ plaques and alleviating amyloid pathology in Alzheimer's disease.

More information: Lau, Shun-Fat, et al. "The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer's disease pathology." Nature Aging (2023): 1-18.

For Research Use Only. Not For Clinical Use.
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