Risk factors for AD include infectious pathogens that can initiate a cascade of chronic neuroinflammatory processes in elderly people. AD can be aggravated by infections of different origin, which implies that it is necessary to accurately diagnose and to provide appropriate treatment based on the impact of an infectious burden on disease progression. Unfortunately, current pharmacotherapy can only reduce the neuropsychiatric symptoms but does not affect the root causes of AD.
Recent research findings also offer hope for developing preventive vaccinations for people. This will reduce the risk of AD rapid progression before it begins because it will eliminate infectious agents that can induce a neurodegenerative process.
The key role of neuroinflammation in AD pathogenesis
Over the past three decades, scientists around the world have been studying the causes of AD. In recent years, various hypotheses have been advanced that propose various mechanisms of pathogenesis and risk factors that are correlated with the disease. The most frequently discussed hypothesis is the amyloid-β hypothesis. It is based on two pathological key aspects in the brains of patients with AD: the neurofibrillary tangles formed with tau-protein inside cells and insoluble clumps of amyloid-β (Aβ) peptide or so-called senile plaques formed outside cells.3
Recent research reveals that Aβ oligomers have antimicrobial properties and, therefore, can be involved in the production and deposition of Aβ that may be indicative of infectious agents.3,4 Three primary contributors have been found in the pathogenesis of AD: neuroinflammatory processes, oxidative stress, and vascular factors.3
As illustrated in the Figure, cumulative infections (bacterial and viral origin), amyloid-β (Aβ) deposits, and an increase in abnormal tau protein lead to a neuroinflammatory process in CNS. Aβ fibrils aggregate into clumps and thereby disrupt the signal transmissions between neurons. Concurrently, neurofibrillary tangles consisting of misfolded tau protein cause the degradation of nerve cells. When resident immune cells such as microglia, macrophages, lymphocytes, and astrocytes are activated, they release pro-inflammatory cytokines (IL-1β, IL-6, IL-18, TNF-α, IFN-γ). This and other inflammatory agents can contribute to additional amounts of Aβ.3,5 As a result of sustained inflammatory insults, a detrimental effect on neurons and the loss of neuronal communication occurs.
The blood-brain barrier can be damaged as a result of oxidative stress caused by microglia and reactive oxygen species. Furthermore, vascular risk factors are known to decline cognitive functions (cerebral hypoperfusion, cerebrovascular lesions, etc) and in combination with an amyloid-relative oxygen species peptide lead to oxidative stress.6 Chronic inflammation may contribute to neurodegeneration and cognitive disorders and it may impair clearance of damaged neuronal proteins in the aged brain.5
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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