# Innate Immune Evasion of Lyme Disease Pathogen Drives Alzheimer-Like Pathology

## TL;DR

This study shows how the Lyme disease bacteria evade the immune system in ways that resemble Alzheimer's disease pathology, offering new insights into both conditions.

## Contribution

The paper reveals a novel mechanism by which Borrelia spp. evade innate immune defenses using Aβ interference, linking it to Alzheimer-like pathology.

## Key findings

- Lyme disease bacteria induce Alzheimer-like molecular changes in the CNS, including altered Aβ levels and complement activation.
- Aβ functions as a pre-opsonin against Borrelia, but the bacteria evade this by blocking Aβ binding and complement attack.
- Borrelia spp. recruit factor H to inhibit immune responses, promoting BBB adhesion and neuroinflammation.

## Abstract

The amyloid β (Aβ) peptide is the main component of amyloid plaques in Alzheimer’s disease (AD). Growing evidence has pointed to a role for Aβ as an antimicrobial peptide (AMP). However, the interactions of Aβ with neurotropic pathogens and host evasion strategies have remained largely unexplored. Using quantitative proteomic analysis of patient cerebrospinal fluid (CSF), advanced biochemical methods, and four different 3D brain models, ranging from blood-brain barrier (BBB) microfluidic systems to 3D neurovascular networks, we show that Lyme neuroborreliosis (LNB) Borrelia spp. induce molecular and immunological alterations in the central nervous system (CNS) that resemble key pathological features of AD. These include upregulation of the complement cascade and a decrease in CSF Aβ levels. By assessing the antimicrobial action of Aβ against Borrelia spp., we demonstrate that Aβ acts as a pre-opsonin by promoting complement activation on microbial surfaces. We also show that LNB Borrelia spp. exhibit unique survival strategies that reduce Aβ binding and block oligomerization, while halting complement attack by recruiting complement regulator factor H. This facilitates bacterial adhesion to the BBB, and modulation of glial and cytokine responses, fostering CNS invasion. Our findings reveal a previously unrecognized mechanism of bacterial immune escape spanning the entire invasion pathway from the BBB to neuronal compartments, demonstrating that LNB Borrelia spp. evade Aβ-mediated antimicrobial action by interfering with opsonization and oligomerization of the peptide. Collectively, these findings provide a direct mechanistic link between pathogen immune evasion, Aβ dynamics, and neuroinflammatory cascades, advancing our understanding of infection-induced neuropathology, offering insights into novel potential therapeutic targets for AD and neuroborreliosis.