A review of the roles of pathogens in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is one of the leading causes of dementia and is characterized by memory loss, mental and behavioral abnormalities, and impaired ability to perform daily activities. Even as a global disease that threatens human health, effective treatments to slow the progression of AD have not been found, despite intensive research and significant investment. In recent years, the role of infections in the etiology of AD has sparked intense debate. Pathogens invade the central nervous system through a damaged blood-brain barrier or nerve trunk and disrupt the neuronal structure and function as well as homeostasis of the brain microenvironment through a series of molecular biological events. In this review, we summarize the various pathogens involved in AD pathology, discuss potential interactions between pathogens and AD, and provide an overview of the promising future of anti-pathogenic therapies for AD.

Keywords: Alzheimer’s disease; bacterial infection; fungal infection; pathogen; viral infection.

FIGURE 1

Mechanisms of pathogens invade the brain and pathogens drive AD pathology. Pathogens invade the CNS through a damaged BBB (①) or nerve trunk (②). Pathogens lead to sustained microglial activation and release of large amounts of inflammatory cytokines, ultimately leading to a chronic neuroinflammatory environment. Additionally, aggregation of Aβ and hyperphosphorylated tau proteins interact with pathogens to exacerbate the pathological events of AD. BBB, blood-brain barrier; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; LRP-1, low-density lipoprotein receptor-ligated protein-1; RAGE, receptor for advanced glycation end products; APP, amyloid precursor protein.

FIGURE 2

Anti-pathogenic/anti-inflammation therapies for AD. Pathogens (virus, bacteria, and fungi) act as risk factors for AD. Pathogens lead to sustained activation of microglia, induce aggregation of Aβ and hyperphosphorylated tau proteins, and release large amounts of inflammatory cytokines, ultimately leading to a chronic neuroinflammatory environment. This suggests that aggressive anti-infective therapies may be beneficial in slowing the progression of AD. AD, Alzheimer’s disease; HSV-1, herpes simplex virus type-1; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; CMV, cytomegalovirus; NSAIDS, nonsteroidal anti-inflammatory drugs.