Virus Infections & Alzheimer's Disease

Alzheimer’s disease (AD) is an irreversible disorder characterized by slow, progressive degeneration and loss of neurons in the areas of the brain responsible for memory formation and storage1. Neuronal cell death eventually leads to loss of memory and thinking skills, and inability to carry out daily tasks.

Memory and other mental functions are severely affected in Alzheimer’s disease.
Scientists have discovered that factors such as age, genetics and environment can cause or increase the risk of developing Alzheimer’s disease. Mounting evidence have implicated Herpes Simplex Virus 1 (HSV-1) infection as an environmental factor involved in the pathogenesis of AD. HSV-1 is a neurotropic virus meaning that it is capable of infecting neurons. Neurotropic viruses are known to be neuroinvasive with the ability to enter, and cause disease and damage in the nervous system.
HSV-1 infections often cause chronic and acute disease. HSV-1 initially infects mucous membranes such as the mouth where it generates viral particles, and subsequently infects the innervating sensory nerve cells and travels towards the brain. HSV-1 is also able to establish latency, such that it remains dormant or inactive in the nerve cells with the potential for reactivation many years after the initial infection has occurred. So once a person is infected with HSV-1, he or she will carry the virus for life. Sometimes the individual may not be aware that they are infected as the virus infection can be asymptomatic.

Global Prevalence of HSV-1

According to a recent poll by the World Health Organization (WHO), an estimated two-thirds of the population under 50 are infected with HSV-1 globally. This statistic could potentially reflect the number of individuals who are at risk for developing AD.

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What are the possible mechanisms whereby HSV-1 infection may trigger neurodegeneration?
Several lines of evidence provide the link between HSV-1 and Alzheimer’s disease. In the recent years, numerous studies have reported the presence of HSV-1 in the brains of patients who have suffered from Alzheimer’s disease. Interestingly, HSV-1 seropositivity is associated with the development of AD, and HSV-1 DNA is often found associated with AD lesions2. In fact, two studies have suggested a link between an increased risk of AD and HSV-1 infection, where being an HSV-1 carrier doubles the risk of developing AD3,4. This risk factor was greater in individuals carrying the ε4 allele of APOE, a gene allele established as a susceptibility factor for AD.
Certain triggers, such as stress, can lead to HSV-1 reactivation where the virus uses cellular machinery to produce viral particles and induce inflammatory responses. Thus the active HSV-1 can cause damage and cell death. HSV-1 reactivation and recurrence can be exacerbated by factors such as aging and suppression of the immune function. It is worth mentioning that HSV-1 DNA is detected at much higher frequency in elderly brains compared to that of younger individuals. This suggests increased HSV-1 occurrence or entry to the brain due to a decline in the immune system as we age. The greater rate of HSV-1 reactivation and HSV-1-induced damage may possibly play a role in the pathogenesis observed in AD.
Further evidence implicating HSV-1 as a risk factor for AD is provided by studies where interactions between HSV-1 and amyloid precursor protein (APP) were demonstrated. APP is the protein that produces amyloid beta (Aβ), the major component of AD plaques in the brain. Aβ is one of the major known causative culprits of AD. Neurotoxic Aβ species are generated from the cleavage of APP by different enzymes. Aβ peptides have a tendency to aggregate and form amyloid plaques. Aβ aggregates and plaques are known to interfere with many cellular processes that lead to neurodegeneration and cell death. Amyloid Plaque
Brain tissue stained with anti-β-Amyloid antibody (cat. no. 803016) that detects amyloid plaques in the brain of Alzheimer’s disease patient.
APP is an integral membrane protein that is commonly found concentrated in the synapses of neurons. APP is thought to function as a regulator of synapse formation and neuronal plasticity. In addition, APP can facilitate transport of cargo via axonal transport. HSV-1 was shown to highjack APP to facilitate viral transport within the infected cell, thus interfering with normal APP transport, distribution and function5. Such dynamic interaction between HSV-1 and APP serves as the mechanistic basis between HSV-1 seropositivity and risk of developing AD.
Of note, a direct interaction between Aβ and HSV-1 has also been demonstrated in cultured neurons and mouse brains infected with the virus6. In this study, HSV-1 infection led to increased levels of Aβ production that resulted from virus-induced upregulation of Aβ-producing enzymes. This data, together with the other findings demonstrates how HSV-1 can directly contribute to the development of amyloid plaques and AD pathology.
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  1. Age-related neuropathology, cognitive decline, and Alzheimer’s disease.
  2. Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: a population-based cohort study.
  3. Reactivated herpes simplex infection increases the risk of Alzheimer’s disease.
  4. Herpes Viruses Increase the Risk of Alzheimer’s Disease: A Meta-Analysis.
  5. Herpes simplex virus dances with amyloid precursor protein while exiting the cell.
  6. Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation.
Contributed by Anna Cartier, PhD.
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