AbstractsBiology & Animal Science

Background and aims: Among those afflicted with dementia more than half suffer from Alzheimer’s disease (AD). Pathological hallmarks of the disease include aggregates of Abeta, so called amyloid plaques, and neurofibrillary tangles (NFTs) made up of hyperphosphorylated cytoskeletal proteins. So far, no single pathological lesion has proven to be the sole cause of this slowly progressive disorder, with declining memory and cognitive deficits, and no curative treatment exists for AD, even though some clinical symptoms can be alleviated. If this disease is to be defeated, probably the treatment must be directed against the disease-causing proteins, rather than downstream clinical manifestations. To find out more about the disease mechanisms, the studies included in this thesis focused on regulation of tau and neurofilament proteins (NFs), both part of the NFTs. Both tau and NFs are hyperphosphorylated in NFTs and the abnormal phosphorylation is dependent on dysregulated kinase and phosphatase activities found in AD. For example, the activity of the kinases GSK-3beta and p70S6K have been found to be increased in AD, and their effects on tau and NFs were investigated in the studies in this thesis. Kinase activity may be regulated by other kinases or by AD pathology in the form of Abeta, increased zinc concentrations or the reoccurrence of cell cycle markers to name a few, both also investigated in these studies. Results and discussion: In Study I, sequential accumulation of Abeta variants and phosphorylated tau epitopes were demonstrated in AD brains. The levels of Abeta showed good correlation with phosphorylated tau; the strength of the correlation depending on the specific tau phosphorylation epitopes. Both Abeta and tau correlated well with different stages of the Braak or CERAD staging systems, which suggests that tau antibodies can be used selectively in AD diagnosis as a complement to morphological evaluations. In Study II, zinc treatment led to increased kinase activities, among them p70S6K and GSK-3beta, and a subsequent increase in tau phosphorylation. Tau translation was also increased through the activation of p70S6K, in accordance with increased tau levels in AD brains. These results indicate that p70S6K can regulate tau on both translational and post-translational levels, while the main effect of other kinases, such as GSK-3beta, is on tau phosphorylation. Many tau kinases are also capable of NF phosphorylation and when N2a cells were treated with zinc, in Study III, an increase in p70S6K activity was observed, together with a concomitant increase in NF phosphorylation. However, when p70S6K activity was blocked with rapamycin, the NF phosphorylation remained unchanged, despite the fact that the p70S6K activity was significantly decreased. Thus, zinc must induce NF phosphorylation in the N2a cells through other kinases. Other factors, such as small heat shock proteins, may influence tau and NF regulation. In Study IV, both Hsp27 and alphaB-crystallin were up-regulated in AD brains, and this correlated with…