Research Summary: Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease

Jacob Umans, Meenu Johnkutty

    As discussed in the disease section of the YNCA Journal, the peptide Amyloid Beta (Aβ) is highly linked to the pathophysiology of Alzheimer’s disease. Plaques form when Aβ clumps together in the synapses of neurons, blocking cell-to-cell communication. Though always viewed in a rather unfavorable light, the study featured in this issue of the YNCA Journal adds new insight into the role of this peptide in Alzheimer’s disease. The research conducted by this Harvard-based team suggests that Aβ, rather than being purely destructive, also acts as an antimicrobial peptide (AMP). Furthermore, the team suggests that “infectious or sterile inflammatory stimuli may drive amyloidosis” (Kumar et al., 2016, p. 1). In other words, the research team posits that infections (by bacteria or fungi, for example) may contribute to the pathology of Alzheimer’s disease.

    When conducting this study, the research team analyzed data from experiments on mice, C. Elegans and in vitro studies of cell cultures. The team analyzed the transgenic (meaning that some genes came from another organism—humans in this case) mouse model of Alzheimer’s disease, 5XFAD, in its resistance to infection by S. Typhimurium bacteria. After injecting S. Typhimurium into the brains of both wild-type and 5XFAD mice (and injecting controls with heat-killed bacteria), the team found that “Survival of Aβ-expressing 5XFAD mice was significantly increased compared to that of nontransgenic littermates (P = 0.009)” (Kumar et al., p. 2, 2016). These results suggest that Aβ provides mice with increased resistance to infection. The graph on the left also demonstrates a statistically different concentration of bacteria in the brains of mice with or without the transgene after a day of exposure to the bacteria. The bacteria were injected into the right hemisphere, explaining the difference in brain bacterial load between the different hemispheres.

    Continuing to analyze the specific effect of Amyloid-β on pathogens, the research team also studied the response of C. Elegans to infection by Candida Albicans fungi. The team used transgenic strains, one of which expressed one isoform of the human Aβ peptide (Aβ42) and green fluorescent protein (GFP). The only transgene expressed in the control strain was GFP. In this portion of the experiment, the researchers found significantly reduced mortality in C. Elegans expressing the transgenic Aβ.

    In this study, the researchers also analyzed both human brain neuroglioma (H4) and Chinese hamster ovary (CHO) cell cultures. They found that 28 hours after infection, cells overexpressing Aβ showed significantly higher survival rates than those not doing so. Furthermore, in analyzing these cells, the researchers found that the concentrations of Aβ within the culture media were approximately one hundred times lower than the minimal inhibitory concentration for Aβ to express fungicidal properties; this finding is consistent with analysis of other AMPs, such as LL-37, which show activity below this threshold. Analysis of agglutination of Candida cells (or the aggregation of cells as a result of AMP activity), which gives LL-37 its antimicrobial properties, showed a statistically significant difference between Aβ-overexpressing cell cultures and control cultures (see graph on left). Aβ acts in a manner similar to LL-37, suggesting that the two proteins may also share a common antimicrobial function. According to the figure cultures of both H4 cells (expressing two different isoforms of the Aβ peptide) and CHO cells which overexpress the Aβ peptide (CHO-CAB) revealed Candida agglutination levels significantly higher than control cultures. In this analysis, the researchers also found that oligomers (short polymers of the Aβ peptide, of approximately 2-30 monomeric units) were found to have a key role in the antimicrobial properties of Aβ. A central role for  oligomers in Aβ protective antimicrobial activities is important because in prevailing amyloidosis  models these species are viewed as intrinsically abnormal and the cause of neurodegeneration in AD.

    In addition to this, the researchers characterized the specific aspect of the Aβ peptide implicated in its antimicrobial properties. Both LL-37 and Aβ share a heparin binding domain, which according to the study allows the Aβ peptide to bind carbohydrates attached to the cell wall of pathogens. As shown in the graphs on the left, treatment with glucan and mannan (two sugars that bind to the heparin domain of Aβ, inhibiting its antimicrobial activity) both increase the percentage of yeast adhesion and decrease yeast agglutination. From these results, the researchers found more evidence supporting the idea that Aβ uses a heparin-binding domain to target microbes. Further research into the mechanisms of action of Aβ suggest that fibrils of Aβ mediate the agglutination observed in cell cultures and animal models.

    Aβ’s antimicrobial properties are consistent with a potential role it can play in vivo. Expression of Aβ in cell culture, nematode, and mouse models was linked to increased host survival. On the other hand, low expression of Aβ resulted in a greater mortality rate among these models. However, the same properties exhibited by Aβ are also related to its pathophysiology, or its physiological processes associated with the formation of disease. For example, LL-37 is necessary for normal immune function and low levels lead to lethal infection. Conversely,  higher levels of LL-37 is cytotoxic to host cells. Thus, if AMPS are not regulated, disease can result.

    The key to making advances in the study of Alzheimer’s Disease lies in further investigation of the properties of Aβ. This study sheds a new perspective on the characteristics of this protein and the alternate forms it can take, both as an antimicrobial peptide and a component of amyloid plaques in Alzheimer’s patients. Uncovering other characteristics of Aβ will allow for a better understanding of the correlation between the antimicrobial properties of the peptide and the pathology of Alzheimer’s disease. Hopefully, with further research, the properties of Aβ can be elucidated in order to open up avenues for future therapeutic intervention in Alzheimer’s disease patients.


This study was made available for analysis and publication in the YNCA Journal through the generosity of Dr. Rudolph E. Tanzi and Dr. Robert Moir. We would also like to thank them for reviewing our summary of their work and making necessary changes.


  1. Kumar, D. K. V., Choi, S. H., Washicosky, K. J., Eimer, W. A., Tucker, S., Ghofrani, J., … Moir, R. D. (2016). Amyloid-peptide protects against microbial infection in mouse and worm models of Alzheimers disease. Science Translational Medicine, 8(340), 340ra72–340ra72. doi:10.1126/scitranslmed.aaf1059

Jacob Umans

Jacob Umans

Jacob Umans is an aspiring physician-scientist in the Stanford University Class of 2020. As a cofounder of the IYNA, he is passionate about science education and hopes to share his excitement about all subfields of neuroscience -- especially glial biology and neuroimmunity -- with students around the world. He hopes to go on to earn an MD/Ph.D. after graduating from Stanford and to use his clinical experience develop a research focused on developing a better understanding of and improved therapies for neurodegenerative diseases. Outside of neuroscience, Jacob is an avid fan of puns, table tennis, and reading.

Meenu Johnkutty

Meenu Johnkutty

This author has not yet uploaded a bio.