Alzheimer’s disease (AD) is characterized by the accumulation of amyloid, which has traditionally been viewed as a toxic protein driving disease progression. However, emerging evidence suggests that amyloid also functions as an antimicrobial peptide (AMP), a component of the innate immune system that helps defend against infections and limit inflammatory damage. Prior studies have shown that amyloid can bind and sequester bacteria, viruses, and microbial toxins, and that exposure to pathogens can rapidly trigger amyloid deposition. Yet most of this work has relied on models that overproduce amyloid, leaving unresolved whether amyloid performs these protective functions under normal physiological conditions.
Dr. Vijaya Kumar proposes to address this question using humanized APP knock-in mice that express physiological levels of amyloid, providing a rigorous model to define its normal biological role in host defense before the onset of advanced amyloid pathology. Preliminary studies from the team demonstrated that amyloid expression improves survival following bacterial and viral brain infections, co-localizes with invading pathogens in brain tissue, and neutralizes bacterial endotoxin (lipopolysaccharide, LPS) while suppressing inflammatory cytokine responses. Together, these findings support a protective immune function for amyloid and provide a foundation for determining how physiological antimicrobial responses may transition to pathological amyloid accumulation.
They hypothesize that amyloid acts as a physiologically relevant antimicrobial peptide that protects the brain from infection-induced inflammation and blood-brain barrier dysfunction, but that chronic or repeated microbial exposure can shift this protective response toward pathological amyloid accumulation and neurodegeneration.
They will investigate this hypothesis using three aims. First, they will determine whether physiological levels of amyloid protect against acute and chronic bacterial infection using Listeria monocytogenes as the primary translational model and Salmonella Typhimurium as a mechanistic validation model, while assessing antimicrobial protection, innate immune responses, blood-brain barrier integrity, and the transition to amyloid pathology. Second, they will determine whether acute and chronic HSV1 infection similarly elicits protective antiviral responses and whether persistent viral exposure promotes neuroinflammation, amyloid deposition, and cognitive impairment. Third, they will investigate the mechanisms by which physiological amyloid neutralizes bacterial endotoxin (LPS), a defining property of classical antimicrobial peptides, and determine whether chronic endotoxin exposure promotes neuroinflammation, blood-brain barrier dysfunction, and pathological amyloid accumulation.
If successful, this work could reshape understanding of amyloid by establishing its physiological role as a context-dependent component of innate immunity and defining how protective antimicrobial responses become maladaptive during disease. These findings could identify new therapeutic strategies that preserve the beneficial functions of amyloid while preventing its transition to pathogenic amyloid deposition.
