E.coli-derived CsgA-peptides stimulate cytokine production in microglia and lead to transient changes in neocortical Aβ-levels in pre-plaque APP/PS1 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 <i>E.coli</i> 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 <i>APP</i> _<i>SWE</i> <i>/PS1</i> _<i>ΔE9</i> mice and age-matched <i>wild type</i> (<i>WT</i>) 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 <i>APP</i> _<i>SWE</i> <i>/PS1</i> _<i>ΔE9</i> and <i>WT</i> 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 <i>APP</i> _<i>SWE</i> <i>/PS1</i> _<i>ΔE9</i> mice and decreasing Aβ₄₀ in the PBS-fraction in <i>WT</i> 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 <i>APP</i> _<i>SWE</i> <i>/PS1</i> _<i>ΔE9</i> 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 <i>APP</i> _<i>SWE</i> <i>/PS1</i> _<i>ΔE9</i> 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.