TY - JOUR
T1 - Amyloid β induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation
AU - Wu, Hai Yan
AU - Hudry, Eloise
AU - Hashimoto, Tadafumi
AU - Kuchibhotla, Kishore
AU - Rozkalne, Anete
AU - Fan, Zhanyun
AU - Spires-Jones, Tara
AU - Xie, Hong
AU - Arbel-Ornath, Michal
AU - Grosskreutz, Cynthia L.
AU - Bacskai, Brian J.
AU - Hyman, Bradley T.
PY - 2010/2/17
Y1 - 2010/2/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77249158836&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77249158836&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4456-09.2010
DO - 10.1523/JNEUROSCI.4456-09.2010
M3 - Article
C2 - 20164348
AN - SCOPUS:77249158836
SN - 0270-6474
VL - 30
SP - 2636
EP - 2649
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 7
ER -