Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, Van Eldik LJ, Norris CM. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer's disease. J Neurosci. 2012 Nov 14;32(46):16129-40. PubMed.
Recommends
Please login to recommend the paper.
Comments
Harvard Medical School and Massachusetts General Hospital
Astrocytes as New Therapeutic Targets in Alzheimer’s Disease
This study by Jennifer Furman and Christopher Norris and colleagues at the University of Kentucky reports that inhibiting astrocytic activation in a mouse model of Alzheimer’s disease (AD) might be an alternative therapeutic approach for attenuating Aβ-induced pathology. This work confirms, once again, that astrocytes play an important role in the progression of the disease, significantly exacerbating amyloid pathology as well as synaptic and cognitive deficits. It also emphasizes the primary function of the calcineurin/NFAT pathway in astrocyte activation and raises the potential use of VIVIT, a specific inhibitor of NFAT activation, in blocking this pathway. Along with our previous data showing that VIVIT reduces Aβ toxicity when directed specifically to neurons (1), these results will hopefully provide clues that will further therapies targeting Aβ activation of calcineurin (CN).
Using a gene transfer approach to overexpress VIVIT specifically in astrocytes, Furman et al. showed that inhibiting the CN/NFAT interaction repaired the morphological alterations that characterize reactive cells in AD transgenic mice. In addition, they observed an overall decrease in glial fibrillary acidic protein, a marker of astrocytosis, confirming the efficiency of VIVIT in vivo. Interestingly, a concomitant reduction of Iba-1 immunoreactivity was detected in microglia, suggesting that proinflammatory mechanisms elicited in both cell types may be closely dependent upon each other. Taken together with the effects on neurons (discussed below), the work indicates that calcineurin is a key modulator of glial-glial and glial-neuronal interactions that are disrupted in the context of Alzheimer's disease.
As suggested by the authors, there is still a debate as to whether, in the context of AD, inflammatory processes are deleterious, protective, or both. In this study, a significant decrease of both soluble Aβ species and amyloid deposits occurred within the brain of VIVIT-treated transgenic mice, which may be related to inhibition of BACE1 expression.
As a consequence of both attenuation of inflammatory processes and lowering the level of neurotoxic amyloid species, cognitive deficits normally detected in 16-month-old transgenic mice were abolished after expression of VIVIT. Electrophysiological recordings also demonstrated a positive effect of VIVIT on synaptic strength and plasticity, so that long-term potentiation (generally accepted as a paradigm underlying memory processes) was restored in treated AD mice.
All together, the results recently published by Furman and colleagues reinforce the idea of a clinical benefit associated with the targeted disruption of the CN/NFAT pathway specifically in astrocytes.
CN/NFAT: One Pathway for Multiple Benefits in AD
The involvement of the calcineurin/NFAT pathway is well characterized in T lymphocytes (2), but the relevance of this particular molecular cascade in the brain has received much less attention. Nonetheless, several recent publications demonstrated that CN is a major actor in neuroinflammatory processes, actively participating in neuronal damage. Indeed, evidence showed CN activity is dysregulated in different pathological contexts (such as Parkinson’s and Huntington’s diseases [3,4]), as well as in Alzheimer’s disease (5,6).
Our group demonstrated a few months ago that the CN/NFAT pathway in neurons exacerbated Aβ-induced synaptic loss in vitro and in vivo (1,6). Recent evidence also implicated activation of the CN/NFAT cascade in the microglial proinflammatory phenotype (7). The present paper described neurotoxic effects associated with the CN pathway astrocytes. These effects are not limited to animal models of AD. Norris and colleagues reported VIVIT overexpression in wild-type animals, thus arguing for a role of the CN/NFAT cascade both in pathological and physiological contexts in vivo.
How can a unique molecular cascade induce distinct effects on several different cell types and within different contexts? Previous work reported that each cellular population in the brain preferentially expresses one NFAT isoform (NFAT3 in neurons, NFAT1 in astrocytes), suggesting that the set of target genes that are transcriptionally regulated by NFAT differs by cell type. Moreover, the ability of NFAT to interact with other transcriptional factors (8,9) may also be a source of fine transcriptional regulation, depending on the cell type and on the physiological or pathological context. It will, therefore, be of great interest to precisely determine the profile of genes regulated in each cell type.
As a conclusion, this elegant study by Christopher Norris and colleagues pointed out for the first time the fundamental role of the calcineurin/NFAT pathway in controlling astrocyte activation in AD. It also demonstrated that strategies aiming at buffering inflammatory processes can be therapeutically relevant toward this fatal neurodegenerative disease.
References:
Hudry E, Wu HY, Arbel-Ornath M, Hashimoto T, Matsouaka R, Fan Z, Spires-Jones TL, Betensky RA, Bacskai BJ, Hyman BT. Inhibition of the NFAT pathway alleviates amyloid β neurotoxicity in a mouse model of Alzheimer's disease. J Neurosci. 2012 Feb 29;32(9):3176-92. PubMed.
Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 1992 Jun 25;357(6380):695-7. PubMed.
Pineda JR, Pardo R, Zala D, Yu H, Humbert S, Saudou F. Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease. Mol Brain. 2009 Oct 27;2:33. PubMed.
Martin ZS, Neugebauer V, Dineley KT, Kayed R, Zhang W, Reese LC, Taglialatela G. α-Synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases. J Neurochem. 2012 Feb;120(3):440-52. PubMed.
Abdul HM, Sama MA, Furman JL, Mathis DM, Beckett TL, Weidner AM, Patel ES, Baig I, Murphy MP, Levine H, Kraner SD, Norris CM. Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci. 2009 Oct 14;29(41):12957-69. PubMed.
Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, Bacskai BJ, Hyman BT. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci. 2010 Feb 17;30(7):2636-49. PubMed.
Nagamoto-Combs K, Combs CK. Microglial phenotype is regulated by activity of the transcription factor, NFAT (nuclear factor of activated T cells). J Neurosci. 2010 Jul 14;30(28):9641-6. PubMed.
Crabtree GR, Schreiber SL. SnapShot: Ca2+-calcineurin-NFAT signaling. Cell. 2009 Jul 10;138(1):210, 210.e1. PubMed.
Ogata K, Sato K, Tahirov TH, Tahirov T. Eukaryotic transcriptional regulatory complexes: cooperativity from near and afar. Curr Opin Struct Biol. 2003 Feb;13(1):40-8. PubMed.
Lee Y, Messing A, Su M, Brenner M. GFAP promoter elements required for region-specific and astrocyte-specific expression. Glia. 2008 Apr;56(5):481-93. PubMed.
High KA, Aubourg P. rAAV human trial experience. Methods Mol Biol. 2011;807:429-57. PubMed.
Make a Comment
To make a comment you must login or register.