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20
Section CELLULAR NEUROSCIENCE
Role of Astroglial Calcium/Calcineurin-Mediated Signaling in Alzheimer's Disease: in Search of Potential Mechanisms and Mediators
D. Lim*
Universita del Piemonte Orientale, Novara, Italy. * Presenting e-mail: dmitry.lim@uniupo.it
Alzheimer's disease (AD) is the most common age-related neurological disorder with an enormous social and economical impact. AD is characterized by progressive loss of memory, social deficit and dementia. Currently, there is no cure or preventive therapy for AD and therefore novel approaches for understanding the AD pathogenesis are desperately needed. Deregulation of calcium homeostasis has been proposed to have a crucial role in pathogenic cascade which leads to neurodegeneration Yet, the possibility that the familial AD (FAD)-associated mutations alongside with the soluble beta-amyloid (Ap) oligomers affect calcium-signaling in astroglial cells, leading thus to neuronal dysfunctions at the early stages of disease, has been largely over-looked. We have dissected a cascade of events by which Ap deregulates calcium homeostasis in hippocampal astrocytes. In details: (i) 100 nM Ap42 leads to an increase in cytosolic calcium; (ii) increased Ca2+ leads to activation of calcineurin (CaN), which in turn (iii) directly activates NFAT to up-regulate IP3R1, and (iv) via interaction with Bcl10 and degradation of IkBa activates NF-kB to up-regulate mGluR5 and IP3R2. Furthermore, ATP-induced IP3R1-mediated Ca2+ release and IP3R1 protein were augmented in the hippocampal astrocytes form 3xTg-AD mice, a well characterized AD mouse model in which persenilin 1 (PS1)-M146V FAD-related mutation is expressed in astrocytes. Finally, we show that mGluR5 staining is augmented in hippocampal astrocytes of AD patients in proximity of Ap plaques and co-localized with accumulation of the p65 NF-kB subunit and increased staining of CaNAa. These data indicate that calcium-dependent activation of CaN and NF-kB mediates the remodeling of astroglial calcium signaling toolkit in AD.
Next, using astrocyte-neuronal co-cultures and astrocyte-conditioned medium (ACM) transfer, we found that Ap42-exposed astrocytes, as well as astrocytes form 3xTg-AD mice produce alterations of dendritic spines and reduce MAP2, PSD95 and Syn38 proteins in cultured neurons in a CaN-dependent manner. Searching for a soluble factor(s) we performed multiplex cytokine assay of ACM, but among 12 cytokines assayed only TGF-p was released at a detectable level. Using qPCR we found that TGF-p2 and TGF-p3 are predominantly expressed at mRNA level. Furthermore, Ap42-induced TGF-p3 mRNA up-regulation as well as release of TGF-p3 from 3xTg-AD astrocytes were blocked by a CaN inhibitor. In cultured hippocampal neurons, treatment with TGF-p2 and TGF-p3, but not TGF-p1, produced reduction of neuronal proteins, suggesting that the p2 and p3 isoforms may play a role in the early AD-related neuronal pathology.
Finally, in order to characterize transcriptional alterations that astroglial cells undergo in the early AD we performed a whole-genome microarray study on cultured hippocampal astrocytes from 3xTg-AD mice using Non-Tg astrocytes as a control. A set of 963 genes was differentially expressed in 3xTg-AD with respect to Non-Tg astrocytes. Gene ontology (GO) analysis revealed that among the up-regulated, the genes involved in nucleotide binding, regulation of transcription and mitochondrial function were significantly overrepresented. Instead, among the down-regulated, the overrepresented genes are involved in cell-cell communication and regulation of synaptic transmission.
Taken together, our data indicate that transcriptional Ca2+/CaN-dependent remodeling of astroglial cells, taking place in the early AD stages, may participate to the development of synaptic and neuronal dysfunction.
Role of Synaptic Plasticity in AMPA Receptor Intracellular Trafficking
F. Coussen*, E. Hangen, F. Cordelières, J. Petersen and D. Choquet
Institut Interdisciplinaire de NeuroScience, UMR5297, Université de Bordeaux, 33077 Bordeaux, France. * Presenting e-mail: fcoussen@u-bordeaux.fr
AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission in the central nervous system. Their abundance at the synapse is essential for the establishment and maintenance of synaptic function. Many studies characterized trafficking of AMPARs in spines at basal state or after induced plasticity. Their synaptic localization is dependent on a highly dynamic exocytosis, endocytosis and plasma membrane trafficking events. Our hypothesis is that synaptic localization of AMPARs is also regulated by their earlier intracellular trafficking. However, AMPARs post-ER traffick-
8 Opera Med Physiol 2016 Vol. 2 (S1)
OM&P
