Human Cathelicidin LL-37 exhibits a dual role in Alzheimer's disease, modulating Aβ aggregation and neuroinflammation

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by Aβ aggregation and neuroinflammation, for which effective therapies remain elusive. Current approaches often fall short in simultaneously enhancing innate immunity and inhibiting Aβ aggregation. Cathelicidin LL-37, an amphipathic host defense peptide, is implicated in immune modulation and inflammatory responses, which are key components of AD progression. Understanding its interaction with Aβ is crucial for identifying novel therapeutic targets that balance immune protection with amyloid modulation.

This conceptual review synthesizes existing literature on the intricate relationship between β-Amyloid (Aβ) and human cathelicidin LL-37 in the context of Alzheimer's disease (AD) pathogenesis. The authors explored the shared characteristics of these peptides, such as their cationic charge and amphiphilic structure, which enable interactions with lipid membranes and influence aggregation. The review focused on how LL-37 modulates Aβ aggregation and the inflammatory response, highlighting their dual roles as protective agents that can become toxic under chronic conditions.

The review highlights that both Aβ and LL-37 are amphipathic molecules with shared motifs, including cationic charge and amphiphilic structure, enabling their interaction with lipid membranes and influencing protein aggregation. LL-37 is found to be upregulated in the brain, where it directly binds to Aβ and modulates its aggregation state. This interaction is complex; initially, both peptides exert protective functions, contributing to innate immunity and host defense. However, under conditions of chronic infection or dysregulation, their interaction can become toxic, exacerbating neuroinflammation and contributing to AD progression. The review emphasizes that LL-37's modulation of the innate immune system and inflammatory response is a critical factor in AD progression, suggesting a delicate balance between beneficial and detrimental effects. The interaction between LL-37 and bacterial LPSs can also lead to stable peptide-lipid complexes, including amyloid-like fibers, further complicating their role.