Abstract
This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer’s disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-β (Aβ) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aβ damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials.
Highlights
This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer’s disease (AD)
A separate line of astrocytoma cells transfected with plasmids expressing the 4 coding sequence had 3-fold more C. pneumoniae elementary body attachment than astrocytoma cells encoding ApoE3. These findings demonstrate that expression of Apolipoprotein E4 (ApoE4) enhances attachment of C. pneumoniae elementary bodies to target host cells, which may enhance infectivity [195]
Cytokines such as IL-1 act on brain endothelial cells to increase the expression of endothelial adhesion molecules and chemokines, including CC chemokine ligand-2 (CCL2), selectins, and intracellular adhesion molecule-1 (ICAM-1), which contribute to blood-brain barrier (BBB) permeability [217]
Summary
Jamieson et al [4] Jamieson et al [42] Baringer and Pisani [271] Gordon et al [272] Itabashi et al [45] Itzhaki et al [49] Lin et al [50] Bertrand et al [273] Cheon et al [274]
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