Immune to Brain Communication Following Real Life Infections in Age and Disease

Despite epidemiological and clinical evidence for systemic infections as a driving force of neuronal dysfunction, mechanistic studies using real live microbial infection in experimental models of normal aging are still limited, and in particular chronic infection models. The studies that have been published to date show that old rats (24 month-old), experience prolonged loss of weight and core body temperature in response to live E. coli, associated with memory deficits [39]. A follow up study showed increased levels of proinflammatory cytokines in the liver and spleen, measured 4 days post infection, which was attenuated by depletion of hepatic and splenic macrophages, but the neuroinflammatory and memory deficits were not affected, suggesting that peripheral macrophages and release of pro-inflammatory cytokines do not play a role in the long-lasting adaptations in the hippocampus [59]. Others have reported that treatment of aged rats with dexamethasone treatment provides neuroprotection against E. coli-associated neurobehavioural and immunological changes via anti-inflammatory and immunomodulatory effects [60]. Studies using live E. coli in normal aged mice have not yet been reported, but infection with an attenuated strain of Mycobacterium bovis, Bacillus Calmette-Guerin (BCG), shows prolonged sickness and depressive like behaviours in 20 month-old mice which can be detected up to 3 weeks post infection [61], but detailed analysis of microglia phenotype and function or immune modulation was not included in this study. Our own studies using a low dose (105 cfu) of S. typhimurium, showed exaggerated and prolonged loss of weight, open field activity and static rod balance, and exaggerated IL-ip production in the hypothalamus, but not hippocampus, in the absence of robust phenotype changes when compared to non-infected aged mice (Hart et al., unpublished). Interestingly, infection of APP/PS1 with the life respiratory pathogen Bordetella pertussis caused increased numbers of Ap plaques and activation of microglia [62], but one of the less expected results was a robust infiltration of CD4+ and CD8+ effector T cells [62]. Interestingly, recurrent infection of three common mouse models for AD, PD, and ALS (i.e., Tg2576, (Thy1)-[A30P] alpha SYN and Tg (SOD1-G93A)) with the most frequent respiratory pathogen, Streptococcus pneumonia, did not alter the course of neurodegeneration or levels of misfolded proteins, despite increased central production of IL-6 [63].

Studies from our own laboratory have shown that AD patients with mild cognitive impairment show a fivefold increased rate of cognitive decline when contracting a systemic urinary tract or respiratory tract infection, especially when serum levels of TNFa are elevated at baseline [64]. These observations are not restricted to normal aging and AD. Clinical manifestation of PD symptoms are increased following recent influenza infection (last infection 0-29 days: OR 3.03, 95 % CI 1.94-4.74), the number of influenza episodes >3 attacks: OR 2.00, 95 % CI 1.45-2.75) and severity of the infection [65]. Apart from bacterial infection, chronic viral infections have also been linked to increased incidence of neurodegeneration, including cytomegalovirus (CMV). This virus is ubiquitously distributed in the human population, and along with other age-related diseases such as cardiovascular disease and cancer, has been associated with increased risk of developing vascular dementia and AD [66, 67]. The underlying mechanisms may include CMV induced immune changes, such as a reduction in naive T cells and/or increased number of T effector memory cells (CD4+/CD27-) and terminally differentiated memory T cells (CD27CD45RA+), following chronic immune activation over a prolonged period [68].

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