Herpes simplex virus interferes with amyloid precursor protein processing.
BACKGROUND
The early events underlying Alzheimer's disease (AD) remain uncertain, although environmental factors may be involved. Work in this laboratory has shown that the combination of herpes simplex virus type 1 (HSV1) in brain and carriage of the APOE-epsilon4 allele of the APOE gene strongly increases the risk of developing AD. The development of AD is thought to involve abnormal aggregation or deposition of a 39-43 amino acid protein--beta amyloid (Abeta)--within the brain. This is cleaved from the much larger transmembranal protein 'amyloid precursor protein' (APP). Any agent able to interfere directly with Abeta or APP metabolism may therefore have the capacity to contribute towards AD. One recent report showed that certain HSV1 glycoprotein peptides may aggregate like Abeta; a second study described a role for APP in transport of virus in squid axons. However to date the effects of acute herpesvirus infection on metabolism of APP in human neuronal-type cells have not been investigated. In order to find if HSV1 directly affects APP and its degradation, we have examined this protein from human neuroblastoma cells (normal and transfected with APP 695) infected with the virus, using Western blotting.


RESULTS
We have found that acute HSV1 (and also HSV2) infection rapidly reduces full length APP levels--as might be expected--yet surprisingly markedly increases levels of a novel C-terminal fragment of APP of about 55 kDa. This band was not increased in cells treated with the protein synthesis inhibitor cycloheximide


CONCLUSIONS
Herpes virus infection leads to rapid loss of full length APP from cells, yet also causes increased levels of a novel 55 kDa C-terminal APP fragment. These data suggest that infection can directly alter the processing of a transmembranal protein intimately linked to the aetiology of AD.
Shipley
Suzanne J
SJ
Faculty of Life Sciences, University of Manchester, Manchester, M60 1QD, UK. s.shipley@postgrad.manchester.ac.uk
Parkin
Edward T
ET
Itzhaki
Ruth F
RF
Dobson
Curtis B
CB
D000544:Alzheimer Disease / Q000821:virology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D045744:Cell Line, Tumor; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D018258:Herpesvirus 2, Human / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma; D009474:Neurons / Q000821:virology; D011498:Protein Precursors / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D011498:Protein Precursors