PMID- 21085580
OWN - NLM
STAT- MEDLINE
DCOM- 20110427
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 11
DP  - 2010 Nov 15
TI  - APP processing induced by herpes simplex virus type 1 (HSV-1) yields several APP 
      fragments in human and rat neuronal cells.
PG  - e13989
LID - 10.1371/journal.pone.0013989 [doi]
LID - e13989
AB  - Lifelong latent infections of the trigeminal ganglion by the neurotropic herpes 
      simplex virus type 1 (HSV-1) are characterized by periodic reactivation. During 
      these episodes, newly produced virions may also reach the central nervous system 
      (CNS), causing productive but generally asymptomatic infections. Epidemiological 
      and experimental findings suggest that HSV-1 might contribute to the pathogenesis 
      of Alzheimer's disease (AD). This multifactorial neurodegenerative disorder is 
      related to an overproduction of amyloid beta (Abeta) and other neurotoxic peptides, 
      which occurs during amyloidogenic endoproteolytic processing of the transmembrane 
      amyloid precursor protein (APP). The aim of our study was to identify the effects 
      of productive HSV-1 infection on APP processing in neuronal cells. We found that 
      infection of SH-SY5Y human neuroblastoma cells and rat cortical neurons is 
      followed by multiple cleavages of APP, which result in the intra- and/or 
      extra-cellular accumulation of various neurotoxic species. These include: i) APP 
      fragments (APP-Fs) of 35 and 45 kDa (APP-F35 and APP-F45) that comprise portions 
      of Abeta; ii) N-terminal APP-Fs that are secreted; iii) intracellular C-terminal 
      APP-Fs; and iv) Abeta(1-40) and Abeta(1-42). Western blot analysis of infected-cell 
      lysates treated with formic acid suggests that APP-F35 may be an Abeta oligomer. The 
      multiple cleavages of APP that occur in infected cells are produced in part by 
      known components of the amyloidogenic APP processing pathway, i.e., host-cell 
      beta-secretase, gamma-secretase, and caspase-3-like enzymes. These findings demonstrate 
      that HSV-1 infection of neuronal cells can generate multiple APP fragments with 
      well-documented neurotoxic potentials. It is tempting to speculate that intra- 
      and extracellular accumulation of these species in the CNS resulting from 
      repeated HSV-1 reactivation could, in the presence of other risk factors, play a 
      co-factorial role in the development of AD.
FAU - De Chiara, Giovanna
AU  - De Chiara G
AD  - Department of Cell Biology and Neuroscience, Istituto Superiore di Sanita, Rome, 
      Italy.
FAU - Marcocci, Maria Elena
AU  - Marcocci ME
FAU - Civitelli, Livia
AU  - Civitelli L
FAU - Argnani, Rafaela
AU  - Argnani R
FAU - Piacentini, Roberto
AU  - Piacentini R
FAU - Ripoli, Cristian
AU  - Ripoli C
FAU - Manservigi, Roberto
AU  - Manservigi R
FAU - Grassi, Claudio
AU  - Grassi C
FAU - Garaci, Enrico
AU  - Garaci E
FAU - Palamara, Anna Teresa
AU  - Palamara AT
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101115
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Peptide Fragments)
RN  - 0 (amyloid beta-protein (1-42))
SB  - IM
MH  - Amyloid beta-Peptides/chemistry/metabolism
MH  - Amyloid beta-Protein Precursor/chemistry/genetics/*metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cells, Cultured
MH  - HeLa Cells
MH  - Herpesvirus 1, Human/genetics/*physiology
MH  - Host-Pathogen Interactions
MH  - Humans
MH  - Microscopy, Confocal
MH  - Mutation
MH  - Neuroblastoma/metabolism/pathology/virology
MH  - Neurons/cytology/*metabolism/*virology
MH  - Peptide Fragments/chemistry/metabolism
MH  - Protein Multimerization
MH  - Rats
MH  - Reverse Transcriptase Polymerase Chain Reaction
PMC - PMC2981559
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/11/19 06:00
MHDA- 2011/04/28 06:00
PMCR- 2010/11/15
CRDT- 2010/11/19 06:00
PHST- 2010/04/23 00:00 [received]
PHST- 2010/10/25 00:00 [accepted]
PHST- 2010/11/19 06:00 [entrez]
PHST- 2010/11/19 06:00 [pubmed]
PHST- 2011/04/28 06:00 [medline]
PHST- 2010/11/15 00:00 [pmc-release]
AID - 10-PONE-RA-18248R1 [pii]
AID - 10.1371/journal.pone.0013989 [doi]
PST - epublish
SO  - PLoS One. 2010 Nov 15;5(11):e13989. doi: 10.1371/journal.pone.0013989.