Dh. Cribbs et al., Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer's A beta peptide, BIOCHEM, 39(20), 2000, pp. 5988-5994
Despite significant progress in the elucidation of the genetic basis of ear
ly-onset familial Alzheimer's disease (AD), the etiology of sporadic cases
remains elusive. Although certain genetic loci play a role in conferring su
sceptibility in some sporadic AD cases, it is likely that the etiology is m
ultifactorial; hence, the majority of cases cannot be attributed to genetic
factors alone, indicating that environmental factors may modulate the onse
t and/or progression of the disease. Head injury and infectious agents are
environmental factors that have been periodically implicated, but no plausi
ble mechanisms have been clearly identified. With regard to infectious agen
ts, 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 carb
oxyl-terminal region of the A beta peptide that accumulates in diffuse and
neuritic plaques in AD. Synthetic peptides were generated and the biophysic
al and biological properties of the viral peptide compared to those of A be
ta. Here we show that this gB fragment forms beta-pleated sheets, self-asse
mbles into fibrils that are thioflavin-positive and ultrastructurally indis
tinguishable from A beta, accelerates the formation of A beta fibrils in vi
tro, 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.