Chronic inflammation and amyloidogenesis in Alzheimer`disease: the role of spirochetes

Absztrakt

The pathological hallmarks of Alzheimer’s disease (AD) consist of β-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes which drive this host reaction are unknown. The cause, or causes, of the vast majority of Alzheimer’s disease cases are unknown. A number of contributing factors have been postulated, including infection. It has long been known that the spirochete Treponema pallidum, which is the infective agent for syphilis, can in its late stages cause dementia, chronic inflammation, cortical atrophy and amyloid deposition. Spirochetes of unidentified types and strains have previously been observed in the blood, cerebrospinal fluid and brain of AD patients and absent in controls. In three of these AD patients spirochetes were grown in a medium selective for Borrelia burgdorferi. In the present study the phylogenetic analysis of these spirochetes was made. We analyzed the sequence of the 16S rRNA gene of the spirochetes grown in medium selective for Borrelia burgdorferi and carried out morphological characterization by transmission electron microscopy. Since diagnostic and serological tests are available for Borrelia burgdorferi, we correlated this with post mortem serological analysis of blood and cerebrospinal fluid (CSF) and were able to detect Borrelia burgdorferi antigens and genes in brain samples from the same cases where the spirochetes were cultivated. Positive identification of the agent as Borrelia burgdorferi sensu stricto was based on genetic and molecular analyses. Borrelia antigens and genes were co-localized with beta-amyloid deposits in these AD cases. To determine whether an analogous host reaction to that occurring in AD could be induced by the same infectious agent, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes. Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to spirochetes. Increased levels of β-amyloid presursor protein (AβPP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes. These observations indicate that, by exposure to bacteria, host responses similar in nature to those observed in AD may be induced. The results of this multifaceted study allow us to conclude that Borrelia burgdorferi like Treponema pallidum in syphilis may persist in the brain and be associated with AD amyloid plaques. The data suggest that Borrelia burgdorferi, perhaps in an analogous fashion to Treponema pallidum, may contribute to dementia, cortical atrophy and amyloid deposition. Furthermore, the present results reinforce previous observations that spirochetes can induce a host reaction with similarities to that seen in AD. The results indicate that bacteria and/or their degradation products may enhance a cascade of events leading to amyloid deposition in AD.

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