Human cathelicidin LL-37's interaction with β-amyloid shifts from protective to neurotoxic in Alzheimer's disease pathogenesis

Alzheimer's disease (AD) is primarily characterized by the aggregation of β-amyloid (Aβ) peptides and chronic neuroinflammation. While Aβ is a central pathological hallmark, it also possesses physiological functions as an evolutionary conserved antimicrobial peptide (AMP), contributing to innate immune defense. The complex interplay between innate immunity, Aβ, and other host defense peptides like human cathelicidin LL-37 in AD pathogenesis remains a critical area of research. Understanding how these peptides transition from protective roles to drivers of pathology is essential, as current AD therapies often focus solely on Aβ clearance, potentially overlooking its beneficial immune functions and the broader immune dysregulation involved.

This comprehensive review synthesizes current understanding of the physiological and pathological interactions between β-amyloid (Aβ) and human cathelicidin LL-37. Researchers analyzed existing literature to explore their dual roles as antimicrobial peptides (AMPs), their modulation of Aβ aggregation, and their contributions to neuroinflammation in the context of Alzheimer's disease (AD). The paper specifically examines how these host defense peptides, while protective under normal physiological conditions, can become detrimental during chronic infection or immune dysregulation, ultimately driving AD pathology. It details their shared mechanisms in pathogen killing, high-affinity binding to bacterial lipopolysaccharides (LPSs) and membrane receptors, and the activation of microglia leading to the release of inflammatory cytokines such as TNF-α and IL-6.

β-amyloid (Aβ), despite its central role in Alzheimer's disease (AD), functions physiologically as an evolutionary conserved antimicrobial peptide (AMP), actively contributing to innate immune defense against pathogens. Human cathelicidin LL-37, another significant AMP, is found to be upregulated in the brain and directly binds to Aβ, thereby modulating its aggregation state. Both Aβ and LL-37 demonstrate high affinity for bacterial lipopolysaccharides (LPSs) and various membrane receptors, exhibiting direct antimicrobial activity against pathogens. This review highlights a critical contextual shift:

Under physiological conditions, both Aβ and LL-37 are protective, but their interaction becomes toxic during chronic infection or immune dysregulation, significantly contributing to AD pathology. Furthermore, LL-37, much like Aβ, can induce neuroinflammation by stimulating human microglia to release key inflammatory cytokines, specifically TNF-α and IL-6. This prolonged neuroinflammatory response, while initially protective against pathogens, ultimately drives the pathological processes underlying AD and other neurodegenerative disorders.