Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer's A beta peptide.
Despite significant progress in the elucidation of the genetic basis of early-onset familial Alzheimer's disease (AD), the etiology of sporadic cases remains elusive. Although certain genetic loci play a role in conferring susceptibility in some sporadic AD cases, it is likely that the etiology is multifactorial; hence, the majority of cases cannot be attributed to genetic factors alone, indicating that environmental factors may modulate the onset and/or progression of the disease. Head injury and infectious agents are environmental factors that have been periodically implicated, but no plausible mechanisms have been clearly identified. With regard to infectious agents, speculation has often centered on the neurotropic herpes viruses, with herpes simplex virus 1 (HSV1) considered a likely candidate. We report that an internal sequence of HSV1 glycoprotein B (gB) is homologous to the carboxyl-terminal region of the A beta peptide that accumulates in diffuse and neuritic plaques in AD. Synthetic peptides were generated and the biophysical and biological properties of the viral peptide compared to those of A beta. Here we show that this gB fragment forms beta-pleated sheets, self-assembles into fibrils that are thioflavin-positive and ultrastructurally indistinguishable from A beta, accelerates the formation of A beta fibrils in vitro, and is toxic to primary cortical neurons at doses comparable to those of A beta. These findings suggest a possible role for this infectious agent in the pathophysiology of sporadic cases of AD.
Cribbs
D H
DH
Department of Neurology, Institute for Brain Aging and Dementia, and Center for the Neurobiology of Learning and Memory, University of California at Irvine, 1109 Gillespie Neuroscience Research Facility, Irvine 92697-4545, USA.
Azizeh
B Y
BY
Cotman
C W
CW
LaFerla
F M
FM
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity / Q000648:ultrastructure; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018259:Herpesvirus 1, Human / Q000472:pathogenicity; D006801:Humans; D020894:Microfibrils / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure; D051381:Rats; D017386:Sequence Homology, Amino Acid; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus