Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection

• Published in: Neuron (Cambridge, Mass.) Mass.), 2018-07, Vol.99 (1), p.56-63.e3
• Main Authors: Eimer, William A., Vijaya Kumar, Deepak Kumar, Navalpur Shanmugam, Nanda Kumar, Rodriguez, Alex S., Mitchell, Teryn, Washicosky, Kevin J., György, Bence, Breakefield, Xandra O., Tanzi, Rudolph E., Moir, Robert D.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - virology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; amyloid-β; Amyloidosis; Amyloidosis - metabolism; Amyloidosis - virology; Animal models; Animals; antimicrobial peptide; Brain; Brain - metabolism; Brain - virology; Cell culture; Cells, Cultured; Central nervous system; Disease Models, Animal; Encephalitis; Encephalitis, Herpes Simplex - metabolism; Encephalitis, Herpes Simplex - virology; Encephalitis, Viral - metabolism; Encephalitis, Viral - virology; Fibrillogenesis; Glycoproteins; Herpes simplex; herpes simplex virus 1; Herpesviridae; Herpesvirus 1, Human; Herpesvirus 6, Human; herpesvirus glycoprotein; human herpesvirus 6; Humans; infection; Infections; Innate immunity; Investigations; Mice; Mice, Transgenic; Microscopy; Neurofibrillary Tangles - metabolism; Neurons; oligomers; Pathogens; Peptides; Plaque, Amyloid - metabolism; Rodents; Roseolovirus Infections - metabolism; Roseolovirus Infections - virology; Transgenic animals; β-Amyloid; β-amyloid peptide
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.06.030

Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer’s disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis. •Human Aβ protects against herpesviridae in AD mouse and 3D human neuronal cell cultures•Fibrilization mediates Aβ antiherpetic activities, entrapping viruses in β-amyloid•Herpesviridae infections dramatically accelerate Aβ-amyloidosis in AD models Eimer et al. report that Aβ traps herpes viruses in insoluble deposits called amyloid. High amyloid accumulation is known to drive Alzheimer’s disease pathology. Hence, this study suggests that active herpes infections in brain may accelerate amyloid deposition and the progression of Alzheimer’s disease.