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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046006-06
Application #
7695015
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Corriveau, Roderick A
Project Start
2005-08-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
6
Fiscal Year
2009
Total Cost
$165,766
Indirect Cost
Name
Charite, Universitaetsmedizin Berlin
Department
Type
DUNS #
320463029
City
Berlin
State
Country
Germany
Zip Code
10117
Krabbe, Grietje; Halle, Annett; Matyash, Vitali et al. (2013) Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 8:e60921
Prokop, Stefan; Miller, Kelly R; Heppner, Frank L (2013) Microglia actions in Alzheimer’s disease. Acta Neuropathol 126:461-77
Locatelli, Giuseppe; Wortge, Simone; Buch, Thorsten et al. (2012) Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat Neurosci 15:543-50
Vom Berg, Johannes; Prokop, Stefan; Miller, Kelly R et al. (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline. Nat Med 18:1812-9
Gertz, Karen; Kronenberg, Golo; Kälin, Roland E et al. (2012) Essential role of interleukin-6 in post-stroke angiogenesis. Brain 135:1964-80
Zhai, Haiyan; Heppner, Frank L; Tsirka, Stella E (2011) Microglia/macrophages promote glioma progression. Glia 59:472-85
Calderón-Gómez, Elisabeth; Lampropoulou, Vicky; Shen, Ping et al. (2011) Reprogrammed quiescent B cells provide an effective cellular therapy against chronic experimental autoimmune encephalomyelitis. Eur J Immunol 41:1696-708
Mirrione, Martine M; Konomos, Dorothy K; Gravanis, Iordanis et al. (2010) Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice. Neurobiol Dis 39:85-97
Grathwohl, Stefan A; Kälin, Roland E; Bolmont, Tristan et al. (2009) Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 12:1361-3
Aslund, Andreas; Sigurdson, Christina J; Klingstedt, Therése et al. (2009) Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses. ACS Chem Biol 4:673-84

Showing the most recent 10 out of 18 publications