Beta-amyloid, tau-protein and cystatin C in the pathophysiology of Alzheimer´s disease

Abstract: Alzheimer´s Disease (AD) is a progressive neurodegenerative dementia characterized by the extracellular accumulation of the beta-amyloid (Ab) peptide into plaques and intracellular phosphorylation and accumulation of tau protein into neurofibrillary tangles (NFT). Inflammation due to astrocytic and microglial activation is one of the ongoing processes in the disease giving rise to cytokine production and oxidative stress. Amyloid beta (Ab) oligomers involvement in microglia activation and subsequent cytokine release was explored in a rat primary microglia cell model. We showed that monomeric and oligomeric but not fibrillary forms of Ab1-40 accounted for IL-1b secretion, while monomeric and oligomeric Ab1-42 induced IL-1a and INF-g release. In parallel, Ab1-42 oligomers, formed at low picomolar concentration, reduced the viability of both primary microglia and immortalized microglial cell line (BV2). We showed that cystatin C decreased the levels of Ab oligomers in vitro, while binding studies suggested that cystatin C bound to the Ab monomers forming a high affinity complex. Finally, the effect of glycogen synthase kinase (GSK)-3b inhibition on tau phosphorylation (p-tau) was investigated in a postnatal rat model. We showed that postnatal tau was physiologically hyperphosphorylated when compared to adult tau, and the levels of p-tau correlated with the activation state of GSK-3b. Furthermore, GSK-3b pharmacological inhibitors reduced postnatal p-tau levels in both cortex and hippocampus. In conclusion, the study on three proteins implicated in the neuropathology of AD elucidated some of the pathophysiological mechanisms behind the multiplicity of the disease. Future studies on each of these proteins may open new avenues towards therapeutic strategies.