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 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.