Although likely to be unrelated to AD, inhibitor further examination of the basis of this lethality may reveal functions of APPswe or PS1dE9 that impact CNS function. Because the reduction in neuronal LRP1 was greatest in the hippocampus, we focused our pathologic analyses on the hippocampus, finding no significant change in the severity of amyloid deposition when LRP1 levels were reduced in the APPswe/PS1dE9 mice. The data shown in Figure ?Figure5C5C document the variability in the number of amyloid deposits in hippocampus between mice that are positive and negative for Cre recombinase. In both groups, the number of animals that were below and above the mean (horizontal line) was similar. Notably, if the number of deposits had been reduced by just 30% (with the same level of variance), then we would have been able to have reached statistical significance (P = 0.

05) with just 10 animals in each group (our n’s were 12 vs. 13). Based on quantification of immunoblots from hemi-brains, we conservatively estimate that the minimum reduction in LRP1 levels would be in the range of 50%. By power calculation, we should have been powered to observe a 30% decrease in amyloid plaque numbers and thus we conclude that reducing LRP1 levels does not produce a proportional decrease in amyloid plaque numbers. Consistent with our findings, Zerbinatti and colleagues reported that increasing the levels of LRP1, via expression of a recombinant mini-receptor, did not produce a proportional increase in amyloid burden [25].

However, this study did note small increases of levels of both soluble and insoluble A?? in the cortex with a more selective increase in soluble A?? in the hippocampus Cilengitide of older mice with high amyloid burden. Our measures of total A?? did not find evidence that reducing LRP1 levels produced a change in the accumulated levels of A??. Zerbinatti and colleagues also noted the appearance of A??42 dimers after extraction in buffers containing 0.1 M carbonate. We have not been able to reliably detect dimeric A?? in our APPswe/PS1dE9 mice at any age and thus we cannot comment as to whether reducing LRP1 reduces the levels of these dimers. Interpreting the outcome of this work is not as straightforward as one would like because the LRP1 levels were not reduced to zero. One issue is that we do not know how much LRP1 must be expressed to sustain amyloidogenesis or whether we should expect changes in amyloid formation in proportion to changes in LRP1 levels. Additionally, the source of the A?? peptides that produce deposits may be neurons that project axons http://www.selleckchem.com/products/Roscovitine.html into the hippocampus as well as local neurons. Within the hippocampus, we observed a near elimination of LRP1 immunoreactivity of neurons of the CA fields.