Amyloid-Beta at the crossroad of neurodegeneration and neuroinflammation

An increasing body of evidence demonstrated that oligomers of Amyloid beta (Aβ) are the most toxic form, which is responsible for neuronal dysfunction, neurodegeneration and cognitive impairment in Alzheimer’s disease (AD). Among many pathological alterations evoked by Aβ, modulation of innate mechanisms of inflammatory response seems to be especially important, in both early and late stages of AD. Misfolded Aβ peptides stimulate Toll-like receptors and activate phagocytic activity of microglia, leading to clearance of Aβ. However, prolonged activation may divert immune system from its beneficial functions and evoke sustained release of inflammatory mediators and reactive oxygen species responsible for degeneration of neurons. On the other hand, inflammation-related processes promote Aβ formation and another AD-related pathological alterations, leading to initiation of self-propagating cycle. Our studies focused on the role of cyclin-dependent kinase 5 in molecular mechanisms of toxicity of Aβ. Experiments on mouse model of AD demonstrated that this kinase may regulate expression of inflammation-related genes in the brain. Depending on age, disease stage and other environmental conditions, neuroinflammatory processes may be beneficial, promoting neuroprotection and neuroregeneration, or can result in neuronal damage. The data suggest that modulation of immune system is a promising protective strategy in AD. This study was supported by The National Science Centre Grant 2011/03/B/NZ3/04549