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a consistent result with in vivo findings of that the pharmacological activation of AMPK by AICAR inhibited the phosphorylation of Tau-Ser396, but increased the phosphorylation of Tau-Ser262.The reduced expression of SIRT1 and the increased expression of p-AMPK in the cortex of SAMP8 5 months group were also observed, as compared to same aged SAMR1 group. These results implicate that AMPK activation may be caused by reduced expression of SIRT1, and which may differentially regulate the phosphorylation of tau protein. Conclusions: A novel finding of significant suppression of SIRT1 and the concomitant increased activity of AMPK in the cortex of SAMP8 aged 2 months without increment of APP expressionis reported. In addition, we found that AMPK activation induce a differential phosphorylation of tau protein in vitro and in vivo models. In conclusion, further investigations are planned to test the hypothesis that the SIRT1 inhibition followed by AMPK activation may be one of the pathogenic mechanisms of tau-related neurodegeneration.

Background: Apolipoprotein E (APOE), a cholesterol carrier associated with atherosclerosis, is a major risk factor for Alzheimer’s disease (AD). The low-density lipoprotein receptor (LDLR) regulates APOE levels in the periphery and in the central nervous system. LDLR is one of the major APOE receptors in the brain and is expressed principally on astrocytes. A number of studies showed that it is involved in amyloid deposition in AD transgenic mice however the findings of previous studies have been controversial.Methods:To investigate the role of LDLR in amyloid deposition we used an APP/PS1 transgenic mouse that develops amyloid plaques with astrocytosis and microgliosis (5xFAD). To elucidate the role of LDLR in relation with APOE we generated 5xFAD transgenic mice on the LDLR or APOE deficient or the APOE/LDLR double deficient background. We have used immunohistochemistry and western blot analysis to analyse the phenotype of the animals. Results: We found that 5xFAD transgenic mice on the LDLR-/-background had increased amyloid plaque deposition compared to 5xFAD control mice. This increase in amyloid plaques was correlated with a significant decrease in astrocytosis and microgliosis in the 5xFAD; LDLR-/-mice. In addition, we found that APOE deletion decreased amyloid plaque formation as expected, but had no effect on astrocytosis or microgliosis in the hippocampus. By comparison 5xFAD; APOE-/-; LDLR-/-double deficient mice had increased amyloid deposition and decreased astrocytosis and microgliosis. Conclusions: The present study shows that LDL deficiency regulates astrocytosis and microgliosis and this effect is independent of APOE, as both 5xFAD; LDLR-/-and 5xFAD; APOE-/-; LDLR-/-mice show reduction in inflammatory response and increase in amyloid deposition compared to control mice. These results demonstrate that LDLR regulates; glial response in this mouse model independently of APOE and aggravates amyloid deposition.

which express either the 4-repeat tau domain with the FTDP-17 mutation Delta-K280 (TauRD/DeltaK280 “pro-aggregation mutant”) or the 4-repeat tau domain with Delta-K280 deletion and two proline mutations in the hexapeptide motifs (TauRD/DeltaK280/I277P/I308 “antiaggregation mutant”). Results: The DeltaK280 mutation accelerates the aggregation of tau, but the inserted proline residues inhibit the tau aggregation in vitro and in cell models. Inducible transgene expression in mice was driven by a forebrain-specific CaMKII promoter in a Tet-Off system and can be suppressed by doxycycline. The pro-aggregation mutant showed aggregated tau in sarkosyl insoluble fractions and Gallyas silver stained neurofibrillary tangles from 3 months onwards, even though the level of the human tau protein was lower than endogenous mouse tau. Tau preparations from pro-aggregation mutant mice revealed PHFs by electron microscopy. Consistent with the tau pathology the neuronal loss was age-dependent and visible in the dentate gyrus as early as 5 months. The immunohistochemisty results showed phosphorylated tau at S262 missorted into the somatodendritic compartment of cortical and hippocampal neurons. The anti-aggregation mutant with a similar expression level as the pro-aggregation mutant did not show aggregated tau or neuronal loss, but missorting into the somatodendritic compartment. The level of synaptophysin, a presynaptic marker and the number of spine-synapses were reduced in the stratum radiatum of the pro-aggregation mutant, but not of the antiaggregation mutant. Six weeks of switching off the tau transgene in the pro-aggregation mutant lead to 90% reduction in the level of soluble human tau protein, to complete reversal of the pathological somatodendritic localization and of phosphorylation in the repeat domain. Remarkably, the aggregation was only partly reversed. The remaining aggregates did not contain the exogenous human tau, but the endogenous mouse tau. Conclusions: The results argue that a toxic species of tau, once introduced into neurons, can “poison” endogenous tau and propagate its aggregation for extended time periods. Supported by MPG and DFG.