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

• DOI: 10.1523/jneurosci.4456-09.2010
• Publication Date: 2010-02-17T18:19:56Z
• Authors: Hai-Yan Wu; Eloise Hudry; Tadafumi Hashimoto; Kishore Kuchibhotla; Anete Rozkalne; Zhanyun Fan; Tara Spires-Jones; Hong Xie; Michal Arbel-Ornath; Cynthia L. Grossk...; Brian J. Bacskai; Bradley T. Hyman
• Keywords: 0301 basic medicine; Dendritic Spines; Green Fluorescent Proteins; Enzyme-Linked Immunosorbent Assay; Mice, Transgenic; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; Neurites; Animals; Humans; Cells, Cultured; Neurons; Cerebral Cortex; Amyloid beta-Peptides; NFATC Transcription Factors; Calcineurin; Embryo, Mammalian; Peptide Fragments; Protein Transport; Postmortem Changes; Culture Media, Conditioned; Mutation; Nerve Degeneration; Calcium; Oligopeptides; Microtubule-Associated Proteins; Subcellular Fractions

Amyloid β (Aβ)-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 Aβ, which surround plaques, induce calcium-mediated secondary cascades that lead to dystrophic changes in local neurites. We show that soluble Aβ 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 Aβ, is sufficient to produce a virtual phenocopy of Aβ-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 Aβ deposits in a mouse model of AD are ameliorated by CaN inhibition, supporting the hypothesis that CaN–NFAT are aberrantly activated by Aβ 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, Aβ appears to mediate the neurodegeneration of AD, at least in part, by activation of CaN and subsequent NFAT-mediated downstream cascades.