Recent findings have shown that not only microtubule-associated protein tau but also amyloid plaques were associated with HSV1 DNA replication. This suggests that HSV-1 promotes the accumulation of toxic Aβ clumps which induces AD-related pathology. Several antiherpetic drugs could be used for treating AD but only for APOE-ε4-carriers. Acyclovir passes through the blood-brain barrier and inhibits viral DNA replication, thereby reducing hyperphosphorylation of p-tau.12,14 The decrease in Aβ deposits reduces levels of HSV1, which minimizes the viral transmission in the brain. Acyclovir has few adverse effects; however, it should be used with caution given its potential for renal failure.
Valtrex (valacyclovir) has shown positive initial results in new indication trials for AD. Compared with placebo, valacyclovir resulted in a decrease in Aβ formation and a smaller increase in 18F-MK-6240 binding to cerebral tau protein. Furthermore, valacyclovir was shown to be effective and safe, which indicates a potential benefit for the future treatment of patients with AD.13
So far, no antimicrobial treatment has been developed for AD. However, it was found that elderly patients with AD frequently have an inflammatory state of gut mucosa because of age-related changes in their gut microbiome (eg, decrease in bacterial diversity.15 In turn, chronic systemic inflammation promote neuroinflammation as result of blood-brain barrier impairment by proinflammatory mediators and bacterial metabolic products.
A team at the University of Chicago utilized a long-term antibiotic mix on experimental rodents.16 The results show a decrease in the growth of amyloid plaques and the activation of microglia. Although, the use of antibiotics for AD may not make sense, the fact of a possible association between gut bacteria and CNS has clinical benefits for further development of new drugs in patients with AD.
Anti-inflammatory drugs also have a role in AD therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of AD.3 It is believed that NSAIDs selectively inhibit the isoforms of COX-2 and attenuate prostaglandin synthesis.17 Even though results showed that the risk of Alzheimer dementia was reduced, a wide range of NSAIDS are not therapeutically effective because they require long-term treatment.18,19
Natural immunosuppressive drugs are a possible means to prevent the onset of neurodegeneration. There is considerable evidence that resveratrol possesses an anti-inflammatory effect combined with dietary supplementation. Lipopolysaccharide was used as an inducer of neuroinflammation in response to peripheral infection.20 Moreover, AD is an infectious disease caused by spirochetes, which form biofilms that in turn initiate the innate immune response. The innate immune system is a first responder—the toll-like receptor 2 generates nuclear factor (NF)-κB and TNF-α, which will likely try to kill the spirochetes in the biofilm, but it cannot penetrate the “slime.”21 NF-κB is also responsible for the generation of amyloid-A, which is antimicrobial and cannot penetrate the biofilm either. Consequently, the accumulation of Aβ leads to the destruction of the cerebral neurocircuitry.
It is significant to note that preventive measures are needed to avoid the risk of premature viral infection in AD patients. There are six pillars of AD prevention: regular exercise, social engagement, healthy diet, mental stimulation, quality sleep, and stress management. These basic health recommendations are associated with maintaining a high-quality life.
Unfortunately, there are no vaccines for HSV-1 or HSV-2, but there is a rich pipeline of candidates. The main difficulties are associated with the virus life cycle and insufficient understanding of the mechanisms of immune control of HSV infection.
At present, AD is a serious global health issue. A large body of evidence shows that infectious pathogens that are responsible for neuroinflammation are observed in elderly people with AD. In-depth studies are needed to determine the root cause of AD. Hopefully, recent discoveries will give rise to effective drug therapies. Eventually, it may be possible to reduce the risk of AD with innovative antiviral therapy and preventive vaccines.
Dr Aliev is President and Founder, International Research Institute, San Antonio, TX; Professor of Pharmacology, First Moscow State Medical University, Moscow; and Professor, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Russia. Dr Bachurin is Scientific Director and Professor of Chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences. Ms Mikhaylenko is a PhD Student, Department of Pharmacology, Institute of Physiologically Active Compounds, Russian Academy of Sciences. Dr Bragin is President and Founder, Stress Relief and Memory Training Center, Brooklyn, NY. Dr Avila -Rodriguez is Leading Researcher, Health Sciences Faculty, Clinical Sciences Department, University of Tolima, Ibague, Colombia. Dr Somasundaram is Professor, Biology Department, Salem University, Salem, WV. Dr Kirkland is Professor, Biology Department and Executive Vice President, Salem University. Dr Tarasov is Chairman, Department of Pharmacology and Pharmacy, First Moscow State Medical University, Moscow. The authors report no conflicts of interest concerning the subject matter of this article.
Acknowledgments—This research was supported within the framework of the grant provided by CSP Ministry of the Health Russian Federation, and by the IPAC RAS State Targets Project # 0090-2019-0005; the Russian Academic Excellence Project “5-100” for the Sechenov University, in Moscow, Russia, also provided support for the research.
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