This project focuses on the hypothesis that one of the critical downstream consequences of Ab induced calcium elevation is activation ofthe only calcium sensitive phosphatase in neurons, calcineurin. Calcineurin is known to have multiple effects, ranging from alterations in cell surface trafficking of neurotransmitter receptors to activation ofthe transcription factor NFAT and initiation of transcriptional cascades. We have observed that neurons cultured from Tg2576 (APPSw) mice develop the same sort of neurodegenerative phenotype that occur near senile plaques in the adult Tg mouse or human Alzheimer brain - loss of dendritic spines, simplification of dendritic arborizations, and neuritic dystrophies. These neurons also show evidence of elevated Calcium and activation of calcineurin. Blockade of calcineurin prevents these neurodegenerative changes. Moreover, conditioned media from these neurons leads to the same neurodegenerative phenotype in wild type neurons. This can be blocked by either immunodepletion of Ab or blockade of calcineurin. Introduction of calcineurin inhibitors in vivo improves plaque-associated neuritic abnormalities in adult transgenic mice. Introduction of a constitutively active form of calcineurin, without Ab present, is sufficient to also lead to this same phenotype. Preliminary data suggest that activation of NFAT is critical for these phenomena, since the NFAT specific inhibitor VIVIT can also block neurodegenerative changes. Our project will extend these observations to determine the specific type of Ab that induces these changes, to examine the mechanism whereby calcineurin activation leads to neurodegeneration, and to come full circle - to critically test the hypothesis that the mechanism of Ab induced neurodegeneration is via activation of calcineurin. Together we will be in an outstanding position to fill in a critical gap in our understanding ofthe mechanisms of Ab induced neurodegeneration.
This project focuses on why neurons become dysfunctional in Alzheimer disease. It centers on a specific enzyme, calcineurin, which is known to be important in normal memory function. We propose to test the idea that amyloid in Alzheimer disease causes abnormalities in calcineurin function, which lead to disruption of synaptic structures critical to memory systems.
|Kim, Taeho; Vidal, George S; Djurisic, Maja et al. (2013) Human LilrB2 is a Î²-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science 341:1399-404|
|Qu, Juan; Matsouaka, Roland; Betensky, Rebecca A et al. (2012) Calcineurin activation causes retinal ganglion cell degeneration. Mol Vis 18:2828-38|
|Wu, Hai-Yan; Hudry, Eloise; Hashimoto, Tadafumi et al. (2012) Distinct dendritic spine and nuclear phases of calcineurin activation after exposure to amyloid-Î² revealed by a novel fluorescence resonance energy transfer assay. J Neurosci 32:5298-309|
|Hudry, Eloise; Wu, Hai-Yan; Arbel-Ornath, Michal et al. (2012) Inhibition of the NFAT pathway alleviates amyloid Î² neurotoxicity in a mouse model of Alzheimer's disease. J Neurosci 32:3176-92|
|Rozkalne, Anete; Hyman, Bradley T; Spires-Jones, Tara L (2011) Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice. Neurobiol Dis 41:650-4|
|Spires-Jones, Tara L; Kay, Kevin; Matsouka, Roland et al. (2011) Calcineurin inhibition with systemic FK506 treatment increases dendritic branching and dendritic spine density in healthy adult mouse brain. Neurosci Lett 487:260-3|