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Infection, Inflammation and Neurodegeneration: A Critical Path to Alzheimer’s disease

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The possibility of an infectious etiology of several chronic diseases, including AD, has long been debated. Alzheimer, himself, over 100 years ago studied Treponema pallidum, the causative agent of syphilis, a spirochete later associated with dementia (Noguchi and Moore, 1913). Sporadic late-onset ...

The possibility of an infectious etiology of several chronic diseases, including AD, has long been debated. Alzheimer, himself, over 100 years ago studied Treponema pallidum, the causative agent of syphilis, a spirochete later associated with dementia (Noguchi and Moore, 1913). Sporadic late-onset Alzheimer’s disease, accounting for ~95% -98% of all cases of Alzheimer’s disease, is thought to arise due to a multi-factorial interplay between genetic and environmental factors. Speculation as to which environmental factors have a great impact on the pathogenesis of this disease has resulted in studies of infectious disease. This is a rational approach as different types of infections have been associated with dementing illnesses, including infection with Treponema pallidum, mentioned previously, as well as Cryptococcus neoformans (Hoffman et al, 2009), measles virus (Frings et al, 2002), and HIV (Zhou et al, 2010). Early studies of infection directly related to Alzheimer’s disease attempted to correlate viral infection with late-onset disease (Pogo et al, 1987). Of the viruses considered were: cytomegalovirus, measles virus, poliovirus, adenoviruses, hepatitis B virus, and the influenza A and B viruses. There was no association with disease determined for these viruses. Later and more recent studies have found evidence for direct brain infection in AD with HSV1 (Itzhaki et al, 1997), Borrelia burgdorferi (Miklossy, 1993), and Chlamydia pneumoniae (Balin et al, 1998, Gerard et al, 2006). There are some reports that even systemic infections may correlate to increased incidence of AD and infection with Helicobacter pylori, the agent of gastric ulcers and Porphyromonas gingivalis, an agent of periodontitis , have been studied in late-onset disease (see Honjo et al, 2009, Kim et al, 2007 for review). Given these reports and the need to identify and understand causative factors for sporadic late-onset AD, much inquiry is needed to determine the mechanisms by which these different infections can initiate and participate in the pathogenesis of AD.
Interestingly, when one considers factors that may drive the accumulation of amyloid and tau in AD, infectious triggers are some of the most significant and logical choices; in particular, the organisms likely to be involved in AD are those that can evade host defenses, gain entry to specific selectively vulnerable regions of the brain, and establish chronic/persistent and/or latent infection. Upon considering the other risk factors found in AD, infection may be the central hub connecting these factors. Currently, evidence from research on Chlamydia pneumoniae, Herpes Simplex Virus 1, and Borrelia burgdorferi in the AD brain, links numerous risk factors with infection to the pathogenesis of AD. Linkage has been identified to risk factors including ApoEe4 expression, chronic neuroinflammation, autoimmune mechanisms, oxidative and mitochondrial damage, cardiovascular factors, diabetes with insulin resistance, trauma to the blood brain barrier and selectively vulnerable brain insult (for reviews see Journal of Alzheimer’s Disease, Vol. 13, #4, May 2008, pgs 357-463). Thus, infection actually may be the overarching “unifying hypothesis” for sporadic late-onset AD, rather than other more mainstream hypotheses.


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