Adaptive Immune System's Chemokine Axis Critically Modulates Neuroinflammation and Progression in Alzheimer's Disease

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by β-amyloid (Aβ) plaque accumulation, hyperphosphorylated p-Tau tangles, and chronic neuroinflammation. This inflammation involves overactivated microglia (brain's resident immune cells) and astrogliosis, leading to cognitive decline. Chemokines, as inflammatory mediators, orchestrate the recruitment of peripheral immune cells into the brain parenchyma, modulating both adaptive and innate immune responses. The breakdown of blood-brain barrier (BBB) integrity, metabolic alterations, and mitochondrial dysfunction further contribute to AD neuropathology. Specifically, ApoE4 is known to trigger brain inflammation and T cell activation in AD patients, highlighting a critical gap in understanding the precise roles of the immune-chemokine axis in disease progression.

This comprehensive review synthesizes existing literature on the immune-chemokine axis in Alzheimer's Disease (AD), meticulously examining the multifaceted roles of the adaptive immune system in neuroinflammation and disease progression. It integrates findings from various preclinical models, including rodent studies, and clinical observations to elucidate how chemokines, expressed by neurons, astrocytes, microglia, and vascular cells, modulate immune cell recruitment and subsequent cellular responses within the brain parenchyma. The review focuses on the impact of peripheral immune cell infiltration, such as neutrophils, T and B cells, and Natural Killer (NK) cells, on AD neuropathology.

The review highlights the dual nature of chemokines in AD, noting their potential for both neuroprotective effects under controlled inflammatory conditions and significant contributions to neurodegeneration in rodent models. It emphasizes that chemokine-triggered recruitment of peripheral immune cells, including regulatory T cells (Treg), CD4+ and CD8+ T cells, B cells, and Natural Killer (NK) cells, can exacerbate Aβ and tau deposition. This infiltration ultimately induces cognitive dysfunction in AD models. > The infiltration of CD4+ and CD8+ T cells into the brain can overactivate microglia, directly contributing to neuroinflammation, though some studies also suggest potential neuroprotective effects depending on the context. The synthesis underscores how high mobilization of peripheral immune cells, coupled with BBB breakdown and metabolic alterations, collectively drives AD neuropathology. ApoE4 is identified as a key trigger for inflammation, leading to overactivation of microglia, astrocytes, and T cells in AD brains.