HSV and Alzheimer's Disease: A Link Worth Investigating

The assignment discusses the possibility of Herpes Simplex Virus (HSV) being a cause or contributor to Alzheimer's disease. HSV is a highly prevalent virus that persists latently in the peripheral nervous system and periodically reactivates with production of active virus. The virus has been detected in the brain of many Alzheimer's patients, but it is unlikely that HSV infection is the only cause of the disease. However, chronic HSV infection may participate in the pathogenic process, especially in individuals carrying the apolipoprotein E ε4 allele. The study suggests a link between HSV infection and Alzheimer's disease pathogenesis, with HSV affecting APP proteolytic processing, transport, phosphorylation, and distribution. The findings open up a novel window to slow or stop the progression of Alzheimer's disease with antiviral strategies.

Herpes simplex virus as a cause of Alzheimer’s disease
In the general population, Herpes Simplex Virus (HSV) is highly prevalent (more than 70% after age 50) . This virus persists
latently in the peripheral nervous system, and periodically reactivates with production of active virus. Herpes Simplex
Encephalopathy (HSE) is a rare but very severe acute infection of the central nervous system. Although it has a very
different course from Alzheimer’s disease (AD), it leads to the occurrence of bilateral hippocampal-inner temporal lesions
resulting in profound verbal memory loss, characteristic of AD. On the basis of this hippocampal and temporal tropism of
the virus, HSV was proposed as a candidate environmental risk factor for AD. Some studies found that HSV has been
detected in the brain of many AD patients, both by direct detection of virus DNA by polymerase chain reaction (PCR) and by
the detection of intrathecal antibodies. However, as the virus was also frequently detected in normal brains of aged
individuals, it is unlikely that HSV infection is the only cause of the disease, but it may participate in the pathogenic process.
The fact that the frequency of HSV DNA positive subjects was not different between AD and control subjects and that
intrathecal IgG antibodies were detected in a similar proportion of patients with AD and elderly controls indicates that
chronic HSV infection alone is not univocally associated with AD. It has been suggested, however, that the risk of
developing AD in subjects positive for HSV DNA presence in the brain who carried apolipoprotein E e4 allele (APOE-e4) was
several fold that of individuals possessing only one or neither of these factors. However, this finding remains controversial
as it has not been confirmed by another study.
Herpes simplex virus (HSV) is a neurotropic double-stranded DNA virus which includes the HSV-1 and HSV-2 subtypes. HSV
is composed of an inner DNA core, a capsid , the tegument, and an outer envelope, which is a lipid membrane containing
glycoproteins. HSV-1 infects 60-80% of people worldwide and causes infectious corneal blindness, the common cold sore
and potentially fatal encephalitis. HSV is one of the leading infectious viral pathogens found in immunocompromised hosts,
such as transplant recipients. HSV induces tissue damage including cell infiltration, perivascular inflammation and syncytial
formation . HSV initially infects the epithelial cells and then enters the sensory nerve terminals. During its life cycle in the
sensory nervous system, HSV travels by retrograde transport to the neuronal cell bodies in the trigeminal ganglia, and then
either enters latency or replicates. Replicated or reactivated HSV travels by anterograde transport out of the cell body to
the central nervous system in addition to the peripheral mucosal membrane.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of neurons and the loss
of intellectual abilities, including memory and cognition. According to the National Institute on Aging, AD afflicts 2.5-4.5
millions Americans and 18 million people worldwide. AD is pathologically characterized by intracellular neurofibrillary
tangles and extracellular senile plaques. While the pathogenesis of AD is still elusive, it is widely recognized that APP plays a
central role in the pathogenesis of AD based on the following evidence: i) amyloid-β precursor protein (APP) is the
precursor to beta-amyloid peptide (Abeta), a main constituent of senile plaques which causes cell death, synaptic defects
and memory impairment ; ii) Disruption of APP-mediated axonal transport contributes to the neurodegeneration
associated with AD ; iii) Aberrant APP phosphorylation results in Abeta production, cell stress and degeneration.
RT-PCR studies reveal the existence of HSV-1 DNA in plaques of frontal and temporal cortices in post-mortem brains of
both sporadic and familial Alzheimer’s disease. The presence of HSV-1 in the brain is considered to be a risk factor for AD in
elderly people who carry the apolipoprotein E ε4 allele. Viral proteins of HSV-1 interact with many AD susceptibility genes
or proteins. In addition, epidemiological study demonstrates that HSV-1 reactivation, as measured by seropositive IgM, is a
high risk factor for AD and that HSV-1 chronic infection contributes to the progressive brain damage characteristic of AD. A
more recent similar study shows that anti-HSV IgG antibody avidity is higher in AD patients and much higher in subjects
with amnestic mild cognitive impairment (a prodromal stage of AD) than in controls, suggesting that seropositve IgG could
be adopted as a biomarker for early diagnosis of amnestic mild cognitive impairment as well as AD. These data suggest a
link between HSV infection and AD pathogenesis. There have been numerous studies focused on deciphering the
mechanisms behind this link.

A plethora of evidence shows that HSV-1 infection affects APP proteolytic processing, transport, phosphorylation and
distribution. A viral envelope glycoprotein B (gB) contains a sequence homologous to the carboxyl-terminal region of Abeta,
a cleavage product of APP . A peptide derived from gB accelerated the formation of Abeta fibrils which were toxic to
primary cortical neurons . Acute HSV-1 infection affects APP proteolytic processing both in vitro and in vivo. APP is co-
isolated with HSV particles from HSV-1 infected Vero cells and isolated HSV-APP particles are able to transport in squid
axon when injected into squid axon, suggesting a role of APP in mediating viral transport. Further experiments in our lab
have confirmed the co-localization of HSV-1 particles with APP inside cells under epifluorescent and electron microscopes.
A time-lapse live confocal imaging reveals that HSV-1 particles travel together with APP inside living cells . This dynamic
interaction between HSV-1 and APP results in pathological consequences: HSV-1 infection decreases the average velocity of
APP vesicles and causes APP mal-distribution in infected cells.]
Compromised transport and mis-localization of APP could contribute to increased APP proteolysis with HSV-1 infection,
which may consequently cause cellular injury. In addition, HSV-1 infection of human neuronal cell line increases the
phosphorylation of tau proteins, the main component of neurofibrillary tangles, one of the hallmarks of AD. A viral kinase,
UL13, which phosphorylates HSV-1 VP22, may phosphorylates human tau proteins [16]. Moreover, treatment of HSV-1-
infected cells with acyclovir, the main antiviral agent used for treating HSV-1 infection by targeting viral DNA
replication,substantially decreases the amount of Abeta and phosphorylated tau protein, two culprits of AD. This finding
not only supports the concept that HSV infection is involved in AD pathogenesis, but also opens up a novel window to slow
or stop the progression of AD with antiviral strategies.
Conclusion
Collectively, HSV-1 infects a wide range of neurons and epithelial cells and transports bidirectionally in neurons and
epithelial cells. HSV functions as intact functional machinery actively usurping a variety of cellular biological machineries by
interacting with cellular proteins for its entry, transcription, DNA replication and egress. HSV infection and repeated
reactivation result in the hyper phosphorylation of tau proteins as well as the disturbance of biogenesis, subcellular
localization, phosphorylation and proteolytic processing of APP. Given the prevalent infection of HSV among people
worldwide, the link of chronic HSV infection to AD and the potential use of HSV as a delivery vector for gene therapy, it is
imperative to dissect the mechanisms for interaction between HSV and cellular proteins that are associated with AD.
Clinical trials for evaluating the efficacy of antiviral drugs in the treatment of AD are urgently needed.