Tanya Watarastaporn

The Aging Brain: A Viral Connection to Alzheimer’s Disease 

March 24, 2021

Introduction

With the contribution of advanced technology, increasingly accessible healthcare, and implementation of health practices, people continue to experience strides in expanding their lifespan relative to people in the past. However, whether we maintain a high quality of life is another issue to consider, especially as many people are concerned about their future susceptibility to neurodegenerative disorders such as Alzheimer’s Disease (AD). Understanding the cause of AD continues to be a significant challenge, resulting in numerous failed clinical trials testing various types of treatments for decades. Thus, as of now, there is no treatment for AD that confers huge benefits for those diagnosed.

As we continue to research AD in hopes of improving current treatments, perhaps more can be done to allocate such efforts to alternate theories about the cause of AD. Of these theories, there is increasing evidence about the involvement of viruses, as researchers continue to come out with studies that implicate them in neurodegenerative diseases.

Introduction to Alzheimer’s Disease (AD)

AD was first discovered in 1906 and named after scientist Alois Alzheimer, who discovered plaques composed of proteins known as amyloid-beta (Aβ), as well as neurofibrillary tangles of proteins known as tau in the post-mortem brain samples of AD individuals. These particular protein aggregates would become well-known pathological hallmarks of AD, a progressive neurodegenerative disorder that specifically targets hippocampal and frontal lobe neurons, accounting for the memory and decision-making deficits seen in those affected. It is the leading cause of dementia, experts predicting that current global prevalence is around 24 million, a figure that may double every 20 years up to the year 2040 (Reitz et al., 2011).

Understanding the mechanisms of AD has stirred decades of debate over what is the “true” hypothesis for its pathogenesis. Based on years of research, a majority of scientists in AD research today continue to assert that age-related accumulation of the sticky protein amyloid-beta (Aβ), which cluster and form the notable plaques which are hallmarks of an individual with AD, are the true cause of AD development. Thus, there is still considerable strength in what is deemed, the “Amyloid Hypothesis”. This theory posits that the gain-of-function accumulation of Aβ to form plaques is the primary factor in causing AD. While this hypothesis is well-studied, a major issue has been a number of studies that have shown that the amyloid plaques do not necessarily correlate with a patient’s degree of cognitive impairment.

Despite the large number of studies done on Aβ and various treatments centered around its clearance or to counteract its effects in AD patients, no cure has come out of years of clinical trials. A recent blow to the AD research community and the amyloid hypothesis is the failure of Biogen’s clinical trials in 2019.

Typical of AD are the pathological accumulation of proteins amyloid-beta and tau, which form the markers of amyloid plaques and neurofibrillary tangles (NFT) respectively, seen in the brains of AD patients post-mortem. In seeing the formation of these markers, researchers have supported the amyloid hypothesis early on, in which these plaques were responsible for pathogenesis. Although the amyloid hypothesis was prominent early on, its popularity has been waning for multiple reasons. In light of findings from experimental models, clinical data, and drug trials, investigating tau as a means of finding a cure to AD has been gaining increased support.

Both mouse and human studies challenge Aβ plaque correlation to AD pathogenesis. In an APP transgenic model of AD, behavioral tests showed that cognitive performance was left intact at ages before and after amyloid plaques developed (Kim et al., 2013). Analogous results have been seen in human studies; researchers have observed multiple cases in which cognitively normal individuals may show amyloid deposits, and conversely, patients diagnosed with AD present much fewer amyloid deposits. Additionally, non-demented elderly patients may show extensive accumulation of plaques comparable to that of their demented counter-parts (Kametani et al., 2018).

Evidence instead supports a closer approximation of clinical observations of AD patients with tau, based on studies of tau’s spatial patterns and its relation to overall dementia severity. Arriagada et al. showed that the pattern of individual cytoarchitectural hierarchical vulnerabilities was correlated with the pattern of NFT accumulation, suggesting a close spatial relationship between NFTs and vulnerability of brain areas affected in AD. In terms of neuronal cell loss implicated in AD, it may share a common mechanism with NFT formation as they usually coincide in the same brain areas, and the progressively expanding anatomical distribution of NFTs to brain regions may be indicative of advancing dysfunction with disease (Maeda et al., 2005).

There is a long history of failed drug trials with regard to AD treatment, there being approximately 4 approved treatments out of 150 drugs from 1998-2017, which are likely only symptomatic versus treating the actual disorder’s progression/development (biopharma-reporter.com).

With reports on the 2019 pipeline of AD-related drugs, treatments that target amyloid-beta still make up a majority of the studies, forming about 32% of the total drugs being tested in phase 3 whereas tau-relates approaches only make up 4% of the trials (Cummings et al., 2009). One of the most well-known failed drug trials is Biogen, whose two phase 3 drug trials EMERGE and ENGAGE failed their endpoint futility tests (Knopman et al., 2020). While one showed a growing positive trend, the other did not show significant difference from the placebo. Until Biogen’s failure, there was great hope for aducanumab, an anti-amyloid-beta drug. While it is possible that based on later analyses that there was significant clinical benefit for subsets of patients that received higher doses, this was still a large blow to the amyloid hypothesis community and attests to the complexity of AD.

While these studies have contributed to some weakening of the amyloid hypothesis compared to its first introduction, other theories have gained gradual strength in light of strong evidence and increasing openness of the AD research community to alternative hypotheses. Of these theories, while facing significant rejection initially, the viral infection theory of there being microbial causes contributing to AD etiology has been gaining reputable traction as the role of the immune system continues to be highlighted as well.

A Viral Infection Theory?

The blood brain barrier (BBB) remains a crucial defense against various toxins, pathogens and other harmful substances trying to access the brain. With aging however, there are alterations that lead to increased disruption of its normal function. As a result, there can be leakage of harmful substances into the brain to exert toxic effects. It is suspected that given the worsening efficiency of the BBB with time, that viruses gain increasing access to the brain, wherein they can potentially enter into neurons and establish long-term latency. There are multiple neurotropic viruses that have been documented to have the ability to do so, with there being a large amount of papers centered around herpes simplex virus 1 (HSV-1), a member of the herpesviridae family.

General Correlation between Viruses and Neurodegeneration

HSV-1 is generally responsible for oral sores, its spread being facilitated by oral secretions or skin sores,  or kissing and sharing objects (ex: toothbrushes, eating utensils). However, even in the absence of sores, HSV-1 can still be spread from person to person. Furthermore, once an individual is infected, there is no cure to permanently rid one of HSV-1. HSV1 can remain dormant in nerve cells, and be reactivated upon various environmental triggers.

For people infected with HSV-1, they can experience periods of viral dormancy, while attacks can be initiated by conditions that weaken the immune system as a downstream effect. Thus, most people experience these outbreaks following fatigue, physical or mental stress, general illness, or any other mechanisms resulting in immunosuppression as the strength of the immune system determines the severity of the invading virus.

Infection with HSV-1 is highly common, as estimates by the World Health Organization suggest that approximately 67 percent of the global population under 50 years old are infected with HSV-1. Furthemore, a large proportion of the infected population will not experience the symptoms.

With HSV-1 being able to cause life-long infections, it makes one wonder whether HSV-1 even in asymptomatic individuals, are still experiencing other symptoms that they are unaware of. After all, even if HSV-1 infection does not generally cause disruption of daily life, infection should still be a concern. After all, there is the possibility that HSV-1 infection of the brain, whether the individual is symptomatic or asymptomatic, could cause neuronal damage based on multiple studies. With increasing neuronal damage, eventually this can pave the way for development of neurodegenerative disorders. Thus, the interest in investigating the cause of neurodegenerative disorders such as AD stem from these observations regarding the mechanisms of HSV-1 infection, and the effects it can exert on the brain as a neurotropic and neuroinvasive virus.

Alzheimer’s Disease

In the case of AD, there has been significant progress to uncover the role of viruses in its pathology. More specifically, there has been an abundance of studies connecting AD to HSV-1. In 1997, this association was made prominent through the efforts of Itzhaki and colleagues, who observed that in the post-mortem brain samples from AD individuals there were significantly higher levels of HSV-1 DNA relative to healthy controls (Itzhaki et al, 1997). This study was ground-breaking in shedding light on the potential of microbial causes of AD as opposed to the long-held dogma of the amyloid hypothesis, bringing special attention to HSV-1 in particular.

Since the publication of Itzhaki’s paper, there have been later studies that continue to implicate herpesvirus infections having a more direct role in AD development. While there has been rejection of the infection theory of AD due to stronger support of the amyloid hypothesis, greater acceptance has been achieved as components of each theory can be linked. For example, while Aβ deposition as the plaques have been posited as a toxic protein symptom of AD, some researchers have questioned whether Aβ may instead have a more protective role.

Thus, some studies explored this possibility, of whether Aβ may have innate immunity characteristics in response to disturbances such as microbial infections. In 2018, Eimer and colleagues contributed to this growing interest in the properties of Aβ, with the claim that perhaps infectious agents can seed and accelerate the Aβ deposition in aging individuals. In reference to HSV-1 specifically, other studies have supported the direct action of HSV-1 infection on amyloid based on in vitro and in vivo models. Compared to uninfected cell supernatants, aggregation of Aβ42, a major component of the Aβ plaques, was catalyzed by the HSV-1 infected counterpart (Ezzat et al., 2019).

These studies have been promising in their consistency with other researchers’ work that allow further questioning of the toxicity of the Aβ plaques, and instead consider whether they play a more protective role. In another intriguing study, researchers utilized a neuronal cell culture model to demonstrate that the promotion of Aβ42 production in response to HSV-1 infection as a mechanism to inhibit increased viral replication (Bourgade et al., 2016).

While there has been past antagonism against the viral infection theory in the field of AD research, more recent studies since then have continued to point to multiple pathways in which the infection and amyloid theories can be linked together mechanistically. Aβ for example, in addition to the studies previously described, can be affected by HSV-1 in other pathways, based on the potential interactions between HSV-1 and the amyloid precursor protein (APP) such that the consequence is Aβ accumulation.

In addition to in vitro and in vivo studies, there has been recent progress in clinically testing the effects of therapetics against herpesviruses, in hopes of combating dementia. Such a study was conducted in Taiwan, enrolling over 30,000 study participants. At the conclusion of their study, they showed promising results as the medications used against HSV-1 (and HSV-2) correlated with lowered risk of dementia (Tzeng et al., 2018). With these findings in mind, there is great hope resting in the results of an ongoing Phase II trial that is evaluating whether daily usage of the anti-viral drug, valacyclovir, against HSV infections will delay cognitive decline in a cohort testing positive for mild AD and HSV infection (Rizzo 2020).

Why Autophagy may be key to Protection

Susceptibility to AD and other neurodegenerative disorders have well-known genetic components. For AD in particular, individuals with the APOE4 allele are predicted to have significantly increased risk relative to those with APOE3 and APOE2. However, genetics makes up only a part of the equation, and there are ways we can modify our risk in terms of environmental or life-style changes. In neurodegeneration, while there are many pathways we can target to confer benefits, there is increasing interest in upregulating the process of autophagy.

Autophagy refers to the evolutionarily conserved process of clearing protein aggregates, dysfunctional organelles, long-lived proteins, and more. This mechanism is important to homeostasis of cells, but has been shown to be dysregulated in AD patients as indicated by increased levels of organelles known as autophagosomes (which is more specific to macroautophagy, one of the main types of autophagy) relative to controls. While the exact mechanism that underlies disruption of autophagy in AD is still being researched, autophagy deficits is indicated by the accumulation of these autophagosomes in neurons of AD patients (Liang and Jia, 2014). Additionally, reduced expression of relevant genes or proteins to autophagy, such as Beclin 1, has also been linked to aging. Furthermore, defects in autophagy have been associated with reduced lifespan in multiple animal models.

In reference to aging however, many studies have reported a downregulating of autophagy or autophagic activity. However, enhancing this process has been associated with benefits such as protection against neurodegeneration, and anti-aging effects. In studies discussing ways to extend lifespan, many of the effects of pharmacological or genetic treatments lead to a downstream effect of inducing autophagy. Though many of the studies on autophagy have been in a laboratory setting, there are ways in which we can directly enhance autophagy in our daily lives.

Of the various functions exerted by autophagy, the most relevant to HSV-1 is autophagy’s role as a defense mechanism against viral infection via promoting pathogen degradation. Compared to other cells that may benefit from alternate defense mechanisms, autophagy is especially crucial for controlling HSV-1 infection/replication in neurons. Thus, in response, HSV-1 has also in turn evolved ways to inhibit autophagy through encoding its own viral proteins that can suppress components important to efficient autophagy.

Autophagy stimulation has been shown to significantly suppress HSV-1 infection in various cell types, as evidenced by assessing HSV-1 genomes and virus titers that indicated that inducing autophagy strongly suppresses HSV-1 infection.

Knowing that enhancing autophagy can be protective against a variety of threats, including against the effects of HSV-1, perhaps protection against AD and even other neurodegenerative disorders can be conferred by mechanisms of increasing autophagy. One of the most strongly supported ways of inducing autophagy has been the mechanisms involved in starvation, which is also linked to increased longevity. Thus, calorie restriction has been getting increased attention as a therapeutic intervention. Based on a study on aged rodents for example, implementing caloric restriction was able to prevent the downregulation of multiple components integral to autophagy (Yang 2014).

This is bolstered by evidence in the literature that food deprivation can result in upregulation of autophagic factors such as Beclin 1, relevant to HSV and neurodegeneration (Bagherniya et al., 2018). Furthermore, in vitro studies have also shown that autophagy stimulation using a starvation medium to incubate mouse embryonic cells have significantly reduced virus levels of HSV-1 relative to unstarved cells (Yakoub et al., 2015). Overall, perhaps inducing autophagy in general, irrespective of means to do so, may be beneficial to dampening effects of HSV, and potentially neurodegeneration.

Conclusion

As researchers continue to explore other theories in explaining the pathology of age-related disorders, there is still a wealth of knowledge to be gained from investigating viruses in detail. As the population continues to age, treatments for neurodegenerative disorders such as AD will be in great need. And with a number of unsuccessful treatments so far, it would be worthwhile to think beyond the current dogma and consider viral targets given more progress in this field.

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