The role of viruses and of APOE in dementia
R.F. Itzhaki, C.B. Dobson, S. Shipley, M.A. Wozniak
Molecular Neurobiology Laboratory, Department of Optometry & Neuroscience, University of Manchester Institute of Science and Technology, Sackville Street, Manchester M60 1QD, UK
Herpes simplex virus type 1 (HSV1) has been implicated in Alzheimers
disease (AD) because of its ubiquity, its propensity for neuronal
latency and because in herpes simplex encephalitis (HSE), it affects
the same brain regions as those mainly damaged in AD. We established,
using PCR, that HSV1 DNA is present in brain of most elderly people,
including AD patients. Subsequently we found that in carriers of the
type 4 allele of the gene for apolipoprotein E (APOE), the virus is a
major risk factor for AD [1,2]. Strong supporting evidence (even if
indirect) comes from our discovery that in five disorders of known
viral origin, APOE determines the outcome of infection. These are:
cold sores [1,2] and HSE [3], caused by HSV1; liver damage caused by
hepatitis C virus [4]; and (in a study by Corder et al. 1998) dementia
and peripheral neuropathy caused by HIV (pre-AIDS). Also, we have
confirmed our PCR detection of the virus in elderly brains in finding
that an appreciable proportion of elderly people have antibodies to
HSV1 in their cerebrospinal fluid (these are known to be very
long-lived after HSE) (submitted). These intrathecal antibodies are
absent, as is HSV1 DNA, in the CNS of younger people. As for other
herpesviruses, we have detected (by PCR) human herpesvirus 6 and
cytomegalovirus DNA in brain of a high proportion respectively of AD
patients [5] and those with vascular dementia [6]; whether the presence
of these viruses confers a risk of the disease (as with HSV1) or is a
consequence is uncertain. Supporting evidence for a viral role in
dementia comes from studies by other groups showing an association of
peripheral infection and its aftermath with decline in cognitive
function in elderly cardiovascular patients and AD patients.
We are now investigating possible mechanisms of interaction of HSV1 and
apoE, and the effect of HSV1 on the breakdown of amyloid precursor
protein in cultured neuronal cells; compared to appropriate control
cells, infected cells have increased amounts of a 55kDa C-terminal
fragment of APP, although that of APP itself decreases, as expected.
1. Itzhaki RF et al., Lancet 1997, 349, 241-244.
2. Lin W-R et al., Alzheimer’s Repts. 1998, 1, 173-178.
3. Lin W-R et al., J. Neurol. Neurosurg. Psychiat. 2001, 70, 117-119.
4. Wozniak MA et al., Hepatology 2002, 36, 456-463.
5. Lin W-R et al., J. Pathol. 2002, 197, 395-402.
6. Lin W-R et al., Neurobiol. Dis. 2002, 9, 82-87.
Key words:
Alzheimer's disease, herpes simplex virus, APOE, intrathecal antibodies, amyloid precursor protein
Problems or questions regarding this site should be directed to
the organiser