Gliosis und Neurogenese - neue Ansätze zur regenerativen Therapie im Alzheimer Maus Modell

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Although neurogenesis persists in restricted regions of the adult mammalian brain such as the subpendymal zone in the lateral wall of the lateral ventricle or the hippocampal subgranular layer, endogenous replacement of neurons does not take place after brain injury in all other brain regions where neurogenesis does not occur into adulthood. However, recently major progress has been made in the attempt to reinstruct neurogenesis after brain injury in the cerebral cortex, an area devoid of adult neurogenesis. Our previous work has identified the transcription factors Olig2 and Pax6 as respectively key anti-neurogenic and pro-neurogenic signals of adult subependymal precursors (Hack et al., 2005). Consistent with its anti-neurogenic function, we found that a strong induction of Olig2 was a common hallmark of both acute (stab-wound) and chronic (cerebral amyloidosis) injuries, while no neurogenic factors were upregulated (Buffo et al., 2005). More importantly, blockade of Olig2 function led to Pax6-upregulation after stabwound injury and resulted in the generation of new neurons from proliferating glial cells in the cerebral cortex (Buffo et al., 2005).We now would like to expand this approach towards neuronal regeneration to mouse models of neurodegenerative lesions. We discovered previously that the gliotic reaction differs profoundly between a model of cerebral amyloidosis and acute injury in regard to the type of glial cells activating Olig2 and their lack of cell proliferation (Buffo et al., 2005). To examine whether the NG2-positive glial cells specifically reacting to amyloidosis can also be instructed towards neurogenesis in vivo we will employ cell type-specific targeting of pseudotyped viral vectors. We have shown that lentiviral vectors with the Mokola pseudotype infect predominantly NG2-positive glial cells that are particularly prominent in the model of cerebral amyloidosis. Conversely, lentiviral vectors with the LMCV pseudotype infect selectively astrocytes in vivo. These viral vectors will be applied to manipulate Olig2 function by the use of dominant-negative constructs or inducing Pax6 or Ngn2 expression in the specific subset of glial cells in the adult cortex of mouse strains showing early amyloidosis or recapitulating all the pathological hallmarks of the Alzheimer disease, including neuronal loss. These experiments will clarify whether the very same molecular machinery that triggers neurogenesis in acute injuries can also instruct endogenous neuronal replacement in the distinct glial subtypes reacting to amyloidosis in chronic neurodegeneration models. Moreover, the viral lineage tracing will further allow us to determine the potential and progeny of distinct types of glial cells in different injuryparadigms.