The APP+PS1 transgenic mouse model of amyloid deposition has features suggesting it may be useful. The first is that even early amyloid deposits have a mild microglial reaction , detectable by complement receptor 3 immunostaining (CD11b a.k.a. mac-1). As the mice age and the deposits mature and become more numerous, there is a further activation of the microglia, and they begin expressing CD45 and, ultimately, MHC-II antigens. However, there is considerable interanimal variability in the extent of this response. While there is temporal coincidence between the age that transgenic mice begin developing memory deficits and the age they develop microglia activation, we have not been able to correlate, within a single treatment group, behavioral performance of individual mice with their degree of microglial activation.
We have tried several manipulations in the hope that it might exacerbate the microglial activation to the point that autotoxicity occurs, and neuron loss becomes manifest in the transgenic beasts. Direct injections of lipopolysaccharide (LPS) into hippocampus caused significant elevations of microglial staining with MHC-II, but no apparent neurotoxicity within 7 days of the injection. Surprisingly, we also found reductions of Aß load in hippocampus in LPS injected mice compared to mice receiving vehicle injections.
We also tried vaccinating mice with Aß, which we initially predicted would cause microglial activation and disrupt memory function prematurely. After 3 and 5 monthly inoculations, we did find further activation of microglia in some of the vaccinated mice, yet at 5 months, mice had intact learning and memory performance on a radial arm water maze. After 9 months, the microglial activation was, if anything, lower than in mice given control vaccines. These mice were also protected from the memory loss found in the control inoculated animals.
A third study tested a nitro-NSAID in an attempt to reduce microglial activation in the brain. To our surprise, the nitro-NSAID ended up activating the microglia and reducing both the Aß load and the amyloid load in cortex and hippocampus when administered systemically.
In conclusion, we have succeeded in modulating the microglial activation in the transgenic mouse model of amyloid deposition. However, thus far, whenever we find activation of microglia, we observe a reduction in the amounts of amyloid deposited. It remains to be determined if a similar activation of microglia might also benefit AD patients, or whether the murine models do not accurately reflect the conditions in the AD brain.
Supported by AG 15490, AG 18478 and AG 20227.
Key words:
Transgenic, amyloid microglia inflammation
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