The big question regarding Alzheimer's disease has always been why only some people suffer this form of dementia. While being overweight clearly increases the risk of dementia, and it is easy to argue that this is because of the chronic inflammation generated by visceral fat tissue, not every overweight individual progresses to the point of Alzheimer's disease. Some people who are not overweight suffer Alzheimer's disease. The condition starts with rising levels of amyloid-β aggregates forming in the brain, thought to be a progressive process occurring over a decade or more prior to any clinical symptoms, but why does this only happen to some people?
The attractive nature of the various infection hypotheses of Alzheimer's disease is that they can answer this question. Only some people with the relevant risk factors suffer Alzheimer's disease because exposure to infectious agents over a lifetime, particularly those that persist in the body, such as various herpesviruses, or lyme spirochetes, is a matter of chance, only loosely related to physical characteristics. In recent years, researchers have identified amyloid-β as an antimicrobial peptide, a part of the innate immune response to pathogens. In this context it makes sense for infection, particularly persistent infection, to be driving the raised levels of amyloid-β necessary to develop Alzheimer's disease.
In today's open access paper, the authors have a different emphasis on infection, suggesting that it is the raised inflammation resulting from infection that drives the progression of Alzheimer's disease. It is quite true that Alzheimer's has a strong inflammatory component. One interpretation of this is that high enough levels of amyloid-β cause dysfunction and cellular senescence in the immune cells of the brain, producing a state of chronic inflammation that in turn encourages the formation of damaging tau aggregates and the onset of the final, severe stage of the condition. But perhaps that inflammation is also a consequence of the infections that drive amyloid-β aggregation.
Among the different risk factors underlying Alzheimer's disease (AD), infection might play a role in late-onset AD. Over the past three decades, infectious agents such as bacteria, viruses, fungi, and protozoa have been reported to trigger the development of AD. The infection hypothesis is not a recent idea. In the 1990s, three laboratories from different countries associated the infection with the etiology of AD. Elderly patients infected with herpes simplex virus (HSV)-1 developed toxic accumulation of amyloid β (Aβ) and phosphorylated (p)-tau protein in the brain. In autopsy cases with histopathologically confirmed AD, spirochetes were found in blood, cerebrospinal fluid, and brain tissue. A national representative survey of US residents involving 1,194 patients with 1,520 hospitalizations for infection with severe sepsis revealed that sepsis survivors were independently associated with substantial and persistent new cognitive impairment and functional disability. All of these studies support the notion that infectious etiology might be a causative factor for the inflammatory pathway associated with AD progression.
The accumulation of misfolded amyloid-β (Aβ) in the brain has been proposed to be the critical triggering event in a complex pathophysiological cascade that leads to AD pathology. The additional physiological role of Aβ as an antimicrobial agent in in vitro and in vivo models has been shown. Studies suggested that Aβ oligomerization, which is considered a pathological development in the context of neurodegeneration, may be a necessary step to potentiate the antimicrobial activity of the peptide. These results raised some important questions about the association between AD and microbial infection. The authors also unveiled the mechanism by which Aβ elicits its antimicrobial property. Aβ binds to a microbe and entraps it by forming amyloid fibrils. The presence of microbes serves as an efficient surface for nucleation of amyloid aggregates, thereby raising the possibility of amyloid deposition.
Even so, the findings raise the question of how the protective function of Aβ fails. The possible answer is microglial dysfunction; accumulation of biologically active peptides following an infection might have not been effectively cleared by microglia in the brain of patients with AD. Additionally, Aβ accumulation in the brain may act as an early toxic event in the pathogenesis of AD. The Aβ monomers, soluble and probably nontoxic, would aggregate into different complex assemblies, including soluble oligomers and protofibrils, with various degrees of toxicity. That may spread throughout the brain, and eventually developed into insoluble amyloid fibrils further assembled into amyloid plaques, which are one of the characteristic histological lesions on AD brains.
Recently, the results from three different groups of investigators demonstrated that sepsis, a life-threatening acute organ dysfunction due to a dysregulated host immune response after infection, induces systemic inflammation that exacerbates the accumulation of Aβ and triggers AD progression. these reports suggest that inflammation is a cardinal component of the pathophysiology of sepsis. Thus, the role of inflammation might be associated with the long-term cognitive impairment observed in sepsis survivors.
Although the molecular cascade that links systemic inflammation and neuroinflammation is still enigmatic, the possible modules that occur after infection, which lead to long-term impairment and brain dysfunction that ultimately trigger AD pathology, may include the following: Invading microorganisms escalate the peripheral Aβ load, a necessary step to neutralize and eliminate the pathogen from the peripheral environment. The peripherally produced Aβ and cytokines enter the central nervous system as systemic inflammation is able to increase blood-brain barrier permeability. An increase in RAGE expression during systemic inflammation also facilitates the transport of Aβ to the central compartment. Finally, the entry of foreign substances triggers brain-immune system crosstalk, which in turn leads to activation of microglia / astrocytes and local production of inflammatory mediators and reactive species. Further comprehension of these mechanisms with newer insights is warranted to develop a strategy for the potential advancement of therapeutics for infection-induced AD progression.