US EPA

1091259 

Journal Article 

Amyloid beta Induces the Morphological Neurodegenerative Triad of Spine Loss, Dendritic Simplification, and Neuritic Dystrophies through Calcineurin Activation 

Wu, HY; Hudry, E; Hashimoto, T; Kuchibhotla, K; Rozkalne, A; Fan, ZY; Spires-Jones, T; Xie, H; Arbel-Ornath, M; Grosskreutz, CL; Bacskai, BJ; Hyman, BT 

2010 

Yes 

Journal of Neuroscience
ISSN: 0270-6474
EISSN: 1529-2401 

30 

7 

English 

Amyloid beta (A beta)-containing plaques are surrounded by dystrophic neurites in the Alzheimer's disease (AD) brain, but whether and how plaques induce these neuritic abnormalities remain unknown. We tested the hypothesis that soluble oligomeric assemblies of A beta, which surround plaques, induce calcium-mediated secondary cascades that lead to dystrophic changes in local neurites. We show that soluble A beta oligomers lead to activation of the calcium-dependent phosphatase calcineurin (CaN) (PP2B), which in turn activates the transcriptional factor nuclear factor of activated T cells (NFAT). Activation of these signaling pathways, even in the absence of A beta, is sufficient to produce a virtual phenocopy of A beta-induced dystrophic neurites, dendritic simplification, and dendritic spine loss in both neurons in culture and in the adult mouse brain. Importantly, the morphological deficits in the vicinity of A beta deposits in a mouse model of AD are ameliorated by CaN inhibition, suorting the hypothesis that CaN-NFAT are aberrantly activated by A beta and that CaN-NFAT activation is responsible for disruption of neuronal structure near plaques. In accord with this, we also detect increased levels of an active form of CaN and NFATc4 in the nuclear fraction from the cortex of patients with AD. Thus, A beta appears to mediate the neurodegeneration of AD, at least in part, by activation of CaN and subsequent NFAT-mediated downstream cascades.