E.coli-derived CsgA-peptides stimulate cytokine production in microglia and lead to transient changes in neocortical Aβ-levels in pre-plaque APP SWE /PS1 ΔE9 and wild type mice.

Epidemiological and pre-clinical data propose that infections can accelerate the cognitive decline in Alzheimer's disease (AD) and other dementias. The implication of infectious agents, and especially the role of E.coli and other amyloid-peptide producing bacteria, on the development and progression of cerebral amyloidosis and neuroinflammation, both key neuropathological characteristics of AD, has only been studied to a limited extent. In this study, recombinant bacterial amyloid surface protein CsgA was injected intracisternally in pre-plaque 8-11-week-old APP SWE /PS1 ΔE9 mice and age-matched wild type (WT) mice. Although less potent than bacterial lipopolysaccharide, CsgA significantly increased the gene expression of inflammatory cytokines, such as tumor necrosis factor, in the neocortex of both APP SWE /PS1 ΔE9 and WT mice, and in cultured microglia. CsgA exposure also induced transient changes in neocortical amyloid-beta (Aβ) peptide levels, increasing the highly fibrillogenic Aβ42 in the guanidine-fraction in APP SWE /PS1 ΔE9 mice and decreasing Aβ40 in the PBS-fraction in WT mice. The changes in Aβ levels had dissipated 24 h post-injection. In line with the only transient changes in Aβ levels and inflammatory gene expression, CsgA did not impact on long term spatial memory in pre-plaque APP SWE /PS1 ΔE9 mice. Our findings highlight a contribution of bacterial amyloid proteins on neuroinflammation and a possible contribution in influencing Aβ-homeostasis during infections. However, findings need to be further elaborated in older APP SWE /PS1 ΔE9 mice in which Aβ plaques are abundant and an inflammatory response already established. Also, the impact of CsgA and other bacterial amyloids should be examined after repeated and/or continuous administration and at different concentrations.