In this month's Aging Cell, researchers show that the herpes simplex virus (HSV), traveling away from the neuronal cell body along axons, is associated with the amyloid precursor protein (APP). This finding offers some new insights into the epidemiologic connection between Alzheimer's disease and HSV-1 (see ARF related news story).
Elaine Bearer and colleagues working at Brown University, Providence, Rhode Island, and the Marine Biology Laboratory, Woods Hole, Massachusetts, noticed the connection when studying transport of new viral particles in the giant axon of the squid. HSV normally travels retrogradely during its infection phase; then, following viral replication, new viral particles travel anterogradely back down neural processes to be released into the mucosal membranes. What determines transport direction is unclear, but recruitment of specific motors by viral proteins may be the key, because particles stripped of their glycoprotein-rich envelope travel only retrogradely.
When first author Prasanna Satpute-Krishnan and colleagues injected squid axons with green fluorescent protein-labeled mature viral particles from infected cytoplasm, the particles moved rapidly in an anterograde direction. To determine what surface proteins contribute to the direction of motion, Satpute-Krishnan examined the particles by electron microscopy, finding that the capsid is surrounded by a protein envelope, which in turn is encased in another membrane. The latter is most likely post-Golgi secretory vesicles, according to the authors. Such vesicles are normally involved in transporting molecules to axonal termini.
APP matures in the Golgi apparatus and has been implicated as a transport motor receptor (see ARF related news story). To see if APP may be present in the viral particles, the authors separated the capsids from their membrane components, then probed the latter for APP. Antibodies to either N- or C-termini of APP revealed an abundant 120 kDa protein in this fraction. In fact, Satpute-Krishnan shows that there are between one thousand and one million APPs per virion, about the same as for true viral proteins, such as the gD envelope protein or the VP22 protein of the viral tegument.
The relationship between APP and HSV is not well understood. One theory links the two with ApoE, which is both a risk factor for AD and binds to gB, a glycoprotein of the viral envelope. But the present findings "provide an alternative hypothesis," according to the authors, who propose that abnormal location, accumulation and processing of APP may result from HSV infection.—Tom Fagan