VCAM1 and APOE Involved in Microglial Clearance of Amyloid-β

One of the characteristics of neurodegenerative conditions such as Alzheimer's disease is the inflammatory activation and dysfunction of microglia. These are cells of the innate immune system distinct to the brain, analogous to macrophages elsewhere in the body. They undertake a similar portfolio of tasks, including chasing down pathogens, destroying errant cells, cleaning up waste and debris such as toxic aggregated proteins found outside cells, and aiding in tissue maintenance and repair. When microglia are in an inflammatory state, they are less inclined to aid in tissue maintenance and clearance of harmful metabolic waste. Further, changes in the signaling environment and other aspects of aging can interfere in the capacity of these cells to clear debris and waste even when they inclined to do so.

In today's research materials, researchers describe some of the mechanisms that regulate clearance of misfolded, aggregated amyloid-β. Aggregation of amyloid-β is a feature of the early stages of Alzheimer's disease, and is thought to cause the onset of later inflammation and tau aggregation. Alzheimer's may thus be a consequence of an age-related failure of the balance between formation and clearance of amyloid-β aggregates. Increased production of amyloid-β may play a role, in its capacity as an antimicrobial peptide in response to infections, and so may reduced drainage of cerebrospinal fluid from the brain, but much of the focus is on reduced clearance by microglia. It is thought that ways to restore the clearance activities of microglia may slow or reverse Alzheimer's disease in its early stages.

Scientists Unveil Promising Target for Alzheimer's Disease Treatment

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects over 50 million people worldwide. A key pathological hallmark of the disease is the accumulation of amyloid-beta (Aβ) plaques in the brain, which leads to progressive decline in cognitive function. Microglia, resident immune cells of the brain, are thought to play a vital role in the clearance of Aβ plaques, a function that is impaired in AD.

The research team sought to investigate how microglia control Aβ clearance and how they become dysfunctional in AD. Through their elegant study, the team discovered that VCAM1, a cell surface protein on microglia, mediates microglial migration towards Aβ and promotes microglial clearance of Aβ. The team also discovered that another protein found in Aβ plaques, APOE, acts in conjunction with VCAM1 to mobilize microglia to Aβ plaques. The team further found that stimulating the "VCAM1-APOE" pathway reduced AD pathology in a mouse model of AD. These findings suggest that proper VCAM1 functioning is critical for microglial migration and clearance of Aβ.

The team also examined VCAM1-expressing microglia in the brain tissue of AD patients. Interestingly, AD patients exhibited elevated levels of soluble VCAM1 in the cerebrospinal fluid, which suggested dysregulated VCAM1-APOE signaling. This observation correlates with reduced clearance of Aβ by microglia. Collectively, the findings of the study implicate VCAM1-APOE signaling in the pathogenesis of AD and identify VCAM1 as a promising target for AD therapy.

The VCAM1-ApoE pathway directs microglial chemotaxis and alleviates Alzheimer's disease pathology

In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial damage-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration.

Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1-ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1-ApoE-dependent microglial functions ameliorates AD pathology.

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