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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease
Deepak Kumar Vijaya Kumar1, Se Hoon Choi1, Kevin J Washicosky1
1Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Abstract:
The amyloid-β peptide (Aβ) is a key protein in Alzheimer's disease (AD) pathology. We previously reported in vitro evidence suggesting that Aβ is an antimicrobial peptide. We present in vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides.
Insights
Alzheimer's disease protein amyloid-beta (Aβ) shows antimicrobial properties, protecting against infections. Its aggregation, previously seen as harmful, is crucial for this protective immune response.
Area of Science:
- Neuroscience
- Immunology
- Microbiology
Background:
- Amyloid-beta (Aβ) is central to Alzheimer's disease (AD) pathology.
- Prior in vitro studies suggested Aβ possesses antimicrobial peptide (AMP) characteristics.
- The in vivo role and functional significance of Aβ's antimicrobial activity remain largely unexplored.
Purpose of the Study:
- To investigate the in vivo antimicrobial functions of amyloid-beta (Aβ).
- To determine if Aβ aggregation is necessary for its antimicrobial activity.
- To elucidate the mechanisms by which Aβ combats microbial infections.
Main Methods:
- In vivo studies utilizing mouse, nematode, and cell culture models.
- Assessment of Aβ expression and its protective effects against fungal and bacterial infections.
- Analysis of Aβ oligomerization states and their correlation with antimicrobial activity.
- Microscopy and molecular techniques to visualize Aβ-pathogen interactions.
Main Results:
- In vivo data demonstrate that Aβ expression confers protection against microbial infections in multiple model systems.
- Aβ oligomerization, a process typically associated with AD pathology, is essential for its antimicrobial functions.
- Aβ oligomers bind microbial carbohydrates, protofibrils inhibit pathogen adhesion, and fibrils entrap microbes.
- Salmonella Typhimurium infection in 5XFAD mice showed rapid Aβ deposition colocalizing with bacteria.
Conclusions:
- Amyloid-beta (Aβ) exhibits significant in vivo antimicrobial activity, suggesting a role in innate immunity.
- Pathogen-induced inflammation or sterile stimuli may contribute to amyloidosis, indicating a dual role for Aβ.
- The findings challenge the solely detrimental view of Aβ aggregation, highlighting its potential protective functions in infection.
