Due to the therapeutic effect of Abeta immunization in mouse models of Alzheimer's disease (AD), clinical trials of active Abeta vaccination in humans have been initiated recently. Although these vaccination strategies appear to slow the cognitive decline in AD patients, some of the vaccinated patients were reported to have experienced neuroinflammatory responses. For this reason, we are planning to utilize mouse models allowing us to clarify mechanism(s) of plaque clearance upon immunization with a special emphasis on the role of microglial cells. We will utilize transgenic mice previously generated in our lab that allow an inducible pharmacogenetic paralysis of microglial cells. The transgene consists of the herpes simplex virus-thymidine kinase (HSV-tk) under the control of the microglia/macrophage-specific CD11b-promoter and induces a paralysis of microglial cells upon administration of the nucleotide analogon ganciclovir at given time points. CD11b-HSV-tk mice have been intercrossed with Abeta plaque forming TgAPP23 mice, a well-characterized transgenic mouse model of AD.
We aim to paralyze microglial cells in doubly transgenic CD11b-HSV-tk x TgAPP23 mice in order to (1) assess the built-up of Abeta plaques/neuropathological alterations as well as cognitive functions in the presence/absence of microglial activation. Moreover, we aim to assess (2) the impact of microglial cells on amyloid plaque clearance upon passive (e.g. by using C- and N-terminal anti-Abeta antibodies) or active Abeta immunization in doubly transgenic mice in the presence/absence of microglial activation.
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