Amyloid beta’s antimicrobial properties protect elderly mice from succumbing to infection with the neurotropic parasite Toxoplasma gondii

Abstract

Data suggest that amyloid beta (Aβ) is a major initiator of Alzheimer's disease (AD) and a highly conserved anti-microbial peptide. Although Aβ accumulation is thought to be detrimental to the brain as a trigger of pathology, like neuroinflammation, efforts to cure AD by clearing Aβ have failed in part because the reactivation of latent disease. Thus, more work is needed to understand how Aβ may be necessary to the brain, where the actions of the adaptive immune system are more restricted compared to other organs in the body. Using the intracellular T.gondii, we are exploring how infection impacts Aβ levels in the brain, how Aβ may combat the parasite, and whether Aβ's importance may change as organisms age.To address whether Aβ is an effective antimicrobial peptide in response to T.gondii infection, in vitro experiments were performed to determine if and how Aβ may protect against infection. Further, in vivo infection studies were performed to assess whether the presence of excess Aβ is helpful during infection with respect to age.We found that exposure to Aβ is effective at protecting cells from invasion by the parasite and those parasites replicate more slowly within cells once they do invade. In vivo, mice with excess Aβ have a lower parasite burden in the brain, indicating that Aβ may either help protect the brain from colonization by an invading pathogen or can help clear the brain of pathogens that have breached the blood-brain barrier. Further, we have found that these protective effects are only beneficial to elderly mice as aged (18mo+) mice with excess Aβ are able to survive T.gondii infection, while their WT littermates are not.These data support the idea that the Aβ could be beneficial as we age. Current work is focused on whether Aβ is toxic to T.gondii or if, as seen in viruses, Aβ traps the pathogen, making it more vulnerable to clearance by the immune system. Future work will include examining how Aβ impacts the functions of the immune system and how pathogens like T.gondii may have evolved ways to subvert the antimicrobial actions of Aβ.