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Astroglial NF-Kb Contributes to White Matter Damage and Cognitive Impairment in a Mouse Model of Vascular Dementia

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Astroglial NF-Kb Contributes to White Matter Damage and Cognitive Impairment in a Mouse Model of Vascular Dementia Saggu et al. Acta Neuropathologica Communications (2016) 4:76 DOI 10.1186/s40478-016-0350-3 RESEARCH Open Access Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia Raman Saggu1, Toni Schumacher1, Florian Gerich1, Cordula Rakers1, Khalid Tai1, Andrea Delekate1 and Gabor C. Petzold1,2* Abstract Vascular cognitive impairment is the second most common form of dementia. The pathogenic pathways leading to vascular cognitive impairment remain unclear but clinical and experimental data have shown that chronic reactive astrogliosis occurs within white matter lesions, indicating that a sustained pro-inflammatory environment affecting the white matter may contribute towards disease progression. To model vascular cognitive impairment, we induced prolonged mild cerebral hypoperfusion in mice by bilateral common carotid artery stenosis. This chronic hypoperfusion resulted in reactive gliosis of astrocytes and microglia within white matter tracts, demyelination and axonal degeneration, consecutive spatial memory deficits, and loss of white matter integrity, as measured by ultra high-field magnetic resonance diffusion tensor imaging. White matter astrogliosis was accompanied by activation of the pro-inflammatory transcription factor nuclear factor (NF)-kB in reactive astrocytes. Using mice expressing a dominant negative inhibitor of NF-kB under the control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter (GFAP-IkBα-dn), we found that transgenic inhibition of astroglial NF-kB signaling ameliorated gliosis and axonal loss, maintained white matter structural integrity, and preserved memory function. Collectively, our results imply that pro-inflammatory changes in white matter astrocytes may represent an important detrimental component in the pathogenesis of vascular cognitive impairment, and that targeting these pathways may lead to novel therapeutic strategies. Keywords: Astrocytes, vascular cognitive impairment, Glia, NF-kB, Diffusion tensor imaging (DTI), Neuroinflammation Introduction that chronic neuroinflammation may also play a detrimen- Vascular cognitive impairment (VCI) is a common neu- tal role in the initiation and progression of VCI. First, rodegenerative disease characterised by impaired cogni- cerebrovascular and cardiovascular diseases, which are tive function attributable to cerebrovascular pathology risk factors for VCI, induce a chronic pro-inflammatory [1]. In its pure form, VCI is the second most common environment, particularly in and around blood vessels form of dementia and represents an important co-factor [4, 5]. Second, increased levels of pro-inflammatory for the development of Alzheimer’s disease and other markers have been detected within white matter lesions neurodegenerative disorders [2]. Neuropathologically, in animal models and post-mortem studies of VCI VCI is characterised by demyelination and axonal loss patients [6, 7], and alterations of blood–brain barrier in- within white matter tracts [3], which has traditionally tegrity are a central and perhaps aggravating element of been attributed to the direct effects of chronic oxygen VCI [8, 9]. Finally, in patients and animal models of VCI, deprivation. However, several lines of evidence suggest reactive gliosis of microglia and astrocytes is present within the white matter [10, 11]. Reactive astrogliosis is a pervasive defence mechanism in response to cerebral * Correspondence: [email protected] injury that may promote neurodegeneration or neuropro- 1German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany tection in a context-dependent manner [12]. However, 2Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str. 25, the roles of astrogliosis and the various inflammatory 53127 Bonn, Germany © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Saggu et al. Acta Neuropathologica Communications (2016) 4:76 Page 2 of 10 cascades mediated by reactive astrocytes in chronic cere- a closed cranial window in anaesthetised mice using bral hypoperfusion and VCI remain poorly understood. PeriCam PSI Laser Speckle Imager and PIMsoft soft- Here, we have used an animal model that recapitulates ware (Perimed). PcomA development was determined many of the neuropathological and behavioural hallmarks by transcardial perfusion with India ink (Pelikan; 10 % of VCI [13]. We demonstrate that reactive astrogliosis in water containing 10 % gelatine), followed by decapi- induces activation of the pro-inflammatory nuclear fac- tation and fixation in 4 % paraformaldehype (PFA). tor (NF)-kB pathway in astrocytes, and that transgenic PcomA was scored as: 0, absent; 1, hypoplastic; 2, trun- inhibition of this pathway confers protection against cal. A single PcomA score was calculated by averaging axonal loss, helps to promote white matter integrity, left and right scores. and preserves cognitive function. Ultra high-field MRI Materials and methods MRI of isoflurane-anaesthetised mice was performed on Animals an 11.7 T horizontal small-bore magnet (Biospec 117/16, All experiments were approved by a local animal welfare Bruker) using a two-element transmit/receive proton committee. We used 10–14 week-old male GFAP-IkBα- (1H) cryocoil (Bruker Biospin). Body temperature was dn mice [14] and their wildtype age-matched male litter- maintained at 37 °C via an integrated water heating sys- mates. Animals were housed in groups (two to five per tem. Respiratory rate was maintained at 70-80 cycles/min. cage) on a 12 h light/dark cycle with food and water Anatomical images were acquired using a rapid acqui- available ad libitum. sition relaxation enhancement (RARE) T2-weighted (T2-w) sequence [echo time (TE) = 0.01 s; repetition Chronic hypoperfusion model time (TR) = 2.5 s; in-plane resolution 45 μm2], and a Gold plated stainless steel microcoils (Sawane) were RARE T1-weighted (T1-w) sequence (TE/TR = 0.01 s/1 s; wrapped around both common carotid arteries in in-plane resolution 45 μm2). White matter integrity was isoflurane-anaesthetised mice [13]. Informed by earlier assessed using an EPI DTI sequence (TE/TR 26/4000 ms; studies that revealed either subtle [15, 16] or very pro- b value 1000 s/mm2; 60 diffusion directions; 5 b0 images; nounced changes [17], we modified the existing model in-plane resolution 100 μm2). by using custom-made coils with an internal diameter of 170 μm. Animals were anaesthetised with isoflurane Immunohistochemistry (1.5 % v/v) and maintained on a heating pad (37 °C). Coronal sections (20 μm) were obtained from PFA-fixed The common carotid arteries were exposed through a hemispheres, blocked with 10 % normal goat serum midline cervical incision, and the microcoils were (Vector Labs) and 0.3 % Triton-X100 (Sigma) in PBS for wrapped around both common carotid arteries. A 1 h, and incubated with primary antibodies in PBS con- 30 min interval was allowed between each microcoil taining 5 % goat serum and 0.05 % Triton overnight at insertion. Sham-treated animals underwent identical 4 °C. The following primary antibodies were used: rabbit procedures except that coils were not implanted. Local anti-GFAP (1:1000; Z0334, Dako), rat anti-GFAP (1:1000; lidocaine gel and intraperitoneal buprenorphine were 13-0300, Invitrogen), rabbit anti-Iba1 (1:500; #019-19741, applied as analgesics. Mice from each litter were rando- Wako), mouse anti-SMI312 (1:500, smi-312r, Covance), mised to either microcoil insertion or sham surgery. All rabbit anti-p65 (1:100; sc-372, Santa Cruz; or #3033, Cell experiments and subsequent data analysis were con- Signaling). Stainings were visualised using secondary anti- ducted in a blinded manner, with respect to genotype bodies from goat conjugated with Alexa Fluor 488, 596 or and treatment. Mice were excluded if visual damage to 647 (1:1000; Invitrogen; 2 h at room temperature). Nuclei the carotid arteries or bleeding during surgery occurred. were stained with Hoechst 33258 (1:1000; Invitrogen). In addition, carotid arteries were inspected for patency at Omission of primary antibodies served as negative con- the end of experiments, and animals with occluded carotid trols. Confocal images were acquired using a confocal arteries were also excluded. laser scanning microscope (LSM 700; Zeiss). Laser speckle perfusion imaging and PcomA assessment Cytokine and NF-kB quantification Animals were anaesthetised with isoflurane (1.5 % v/v), Mice were sacrificed, and the corpus callosum was dis- and the skull was exposed through a midline incision. A sected and stored in liquid nitrogen. Samples were homo- cranial window was created and closed by gluing a glass genised in PBS containing protease/phosphatase inhibitor coverslip onto the skull and adhering the skin to the (Thermo Scientific) using a Precellys 24 homogeniser coverslip rim. For imaging, mice were anaesthetised with (Peqlab), and lysed in RIPA buffer (25 mM TRIS, 150 mM isoflurane (1 % v/v) and fixed within a stereotaxic
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