The Impact of ApoE4 on Neutrophil-Microglia Interactions in Alzheimer's Disease

Alzheimer's disease (AD) is the most common type of dementia, exerting a significant social and economic impact. Its hallmark neuropathological features include β-amyloid (Aβ) deposition, tau hyperphosphorylation, and the loss of synapses and neurons. Recent studies suggest that chronic inflammation mediated by local and peripheral immune cells also plays a critical role in the pathogenesis of AD.

Circulating immune cells play a key role in AD pathogenesis, but their precise functions remain unclear. Research by Rosenzweig et al. revealed that, in APOE4-carrying females, a subset of neutrophils secreting interleukin (IL)-17 suppressed the neuroprotective functions of microglia. Blocking IL-17 signaling or knocking out APOE4 in neutrophils restored microglial function and reduced amyloid pathology in mice.

Neutrophils are the most abundant white blood cells in human blood, capable of rapidly migrating to inflammatory tissues. Under sterile inflammatory conditions, neutrophils release potentially harmful inflammatory mediators and form neutrophil extracellular traps (NETs). Previous studies have shown that neutrophils migrate to the brains of AD patients and transgenic mice with AD-like diseases, exacerbating disease progression by obstructing cerebral capillaries. Notably, early transient depletion of neutrophils in AD animal models significantly reduced neuropathological markers and improved memory function.

Soluble oligomeric Aβ42 peptides induce integrin-dependent adhesion of human and mouse neutrophils, leading to blood-brain barrier dysfunction. Therapeutic blockade of the integrin LFA-1 improved cognitive function in AD mice and reduced the severity of neuropathology.

In circulating neutrophils, AD patients exhibit a hyperactivated phenotype. Single-cell transcriptomics by Rosenzweig et al. identified a novel subset of neutrophils in APOE4-carrying females associated with cognitive impairment, showing co-expression of IL-17 and IL-1 along with upregulated immunosuppressive cytokines IL-10 and TGF-β. This suggests that these neutrophils may exert immunomodulatory functions in APOE4 carriers.

Rosenzweig and colleagues filled a knowledge gap regarding neutrophil-microglial interactions by observing interactions between CD66b+ neutrophils and IBA1+ microglia in post-mortem AD patient brains. Furthermore, in transgenic amyloidopathy mouse models, APOE4 deficiency reduced inhibitory neutrophil phenotypes, improved cognitive function, and limited amyloid pathology progression.

IL-17F was shown to recruit immunosuppressive neutrophils when injected directly into mouse brains. Flow cytometry revealed reduced neutrophil infiltration in the brains and choroid plexus of IL-17F-blocked mice. Additionally, neutrophils co-expressing CitH3 and IL-17 were detected in the brains of female APOE ε3/4 carriers, further supporting their role in AD.

Although studies have shown a significant correlation between MGnD clusters and tau pathology, Rosenzweig et al. only used amyloidopathy models (such as APP/PS1 and 5×FAD) and did not evaluate the impact of IL-17F blockade on tau pathology. Previous research suggests that neutrophil depletion significantly reduces amyloid burden and tau hyperphosphorylation in 3×Tg-AD mice, which develop both tau and amyloid pathologies.

The research team led by Oleg Butovsky demonstrated the critical role of the IL-17F–IL-17RA axis in mediating neutrophil-microglial interactions in cognitively impaired APOE4-carrying females and amyloidopathy mice. Targeting IL-17F may benefit female APOE4 carriers who respond poorly to current anti-Aβ therapies. However, future studies should further explore gender differences in AD patients and better define clinical therapeutic strategies for AD.