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Galectin-3 Promotes Aβ Oligomerization and Aβ Toxicity in a Mouse Model of Alzheimer’S Disease

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Galectin-3 Promotes Aβ Oligomerization and Aβ Toxicity in a Mouse Model of Alzheimer’S Disease Cell Death & Differentiation (2020) 27:192–209 https://doi.org/10.1038/s41418-019-0348-z ARTICLE Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer’s disease 1,2 1,3 1 1 1,2 4,5 Chih-Chieh Tao ● Kuang-Min Cheng ● Yun-Li Ma ● Wei-Lun Hsu ● Yan-Chu Chen ● Jong-Ling Fuh ● 4,6,7 3 1,2,3 Wei-Ju Lee ● Chih-Chang Chao ● Eminy H. Y. Lee Received: 1 October 2018 / Revised: 13 April 2019 / Accepted: 2 May 2019 / Published online: 24 May 2019 © ADMC Associazione Differenziamento e Morte Cellulare 2019. This article is published with open access Abstract Amyloid-β (Aβ) oligomers largely initiate the cascade underlying the pathology of Alzheimer’s disease (AD). Galectin-3 (Gal-3), which is a member of the galectin protein family, promotes inflammatory responses and enhances the homotypic aggregation of cancer cells. Here, we examined the role and action mechanism of Gal-3 in Aβ oligomerization and Aβ toxicities. Wild-type (WT) and Gal-3-knockout (KO) mice, APP/PS1;WT mice, APP/PS1;Gal-3+/− mice and brain tissues from normal subjects and AD patients were used. We found that Aβ oligomerization is reduced in Gal-3 KO mice injected with Aβ, whereas overexpression of Gal-3 enhances Aβ oligomerization in the hippocampi of Aβ-injected mice. Gal-3 expression shows an age-dependent increase that parallels endogenous Aβ oligomerization in APP/PS1 mice. Moreover, Aβ oligomerization, Iba1 expression, GFAP expression and amyloid plaque accumulation are reduced in APP/ PS1;Gal-3+/− mice compared with APP/PS1;WT mice. APP/PS1;Gal-3+/− mice also show better acquisition and retention performance compared to APP/PS1;WT mice. In studying the mechanism underlying Gal-3-promoted Aβ oligomerization, we found that Gal-3 primarily co-localizes with Iba1, and that microglia-secreted Gal-3 directly interacts with Aβ. Gal-3 also interacts with triggering receptor expressed on myeloid cells-2, which then mediates the ability of Gal-3 to activate microglia for further Gal-3 expression. Immunohistochemical analyses show that the distribution of Gal-3 overlaps with that of endogenous Aβ in APP/PS1 mice and partially overlaps with that of amyloid plaque. Moreover, the expression of the Aβ-degrading enzyme, neprilysin, is increased in Gal-3 KO mice and this is associated with enhanced integrin-mediated signaling. Consistently, Gal-3 expression is also increased in the frontal lobe of AD patients, in parallel with Aβ oligomerization. Because Gal-3 expression is dramatically increased as early as 3 months of age in APP/PS1 mice and anti-Aβ oligomerization is believed to protect against Aβ toxicity, Gal-3 could be considered a novel therapeutic target in efforts to combat AD. Introduction Senile plaque is one of the two pathological hallmarks of Alzheimer’s disease (AD), and amyloid-β peptides are the Edited by L. Greene major components of senile plaques. Aβ is generated Supplementary information The online version of this article (https:// from sequential and proteolytic cleavages of the amyloid doi.org/10.1038/s41418-019-0348-z) contains supplementary material, precursor protein (APP) by β-secretase and γ-secretase which is available to authorized users. * Eminy H. Y. Lee 4 Faculty of Medicine, National Yang-Ming University School of [email protected] Medicine, Taipei, Taiwan 5 Department of Neurology, Neurological Institute, Taipei Veterans 1 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan General Hospital, Taipei, Taiwan 2 Graduate Institute of Life Sciences, National Defense Medical 6 Neurological Institute, Taichung Veterans General Hospital, Center, Taipei, Taiwan Taichung, Taiwan 3 Institute of Neuroscience, National Cheng-chi University, 7 Institute of Clinical Medicine, National Yang-Ming University Taipei, Taiwan School of Medicine, Taipei, Taiwan Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of. 193 [1]. Individual Aβ42 monomers form soluble oligomers Results of different molecular weight [2], and these oligomers further aggregate to form insoluble Aβ fibrils and amyloid Intra-hippocampal Aβ injection causes Aβ plaques [3]. The evidence indicates that Aβ oligomers oligomerization perturb the integrity of membrane lipid bilayers, increase ion permeability, cause calcium influx and consequently We first examined whether exogenous Aβ injection pro- affect synaptic transmission and neuronal viability [4, 5]. duces Aβ oligomers in the hippocampus. Mice received Conversely, disaggregation of Aβ oligomers decreases intra-hippocampal NH4OH or Aβ injection and were sacri- Aβ-induced inflammation and rescues cognitive deficits ficed 14 days later. Their hippocampal tissues were dis- in APP/PS1 mice [6]. Thus, soluble Aβ oligomers are sected and subjected to Western blot analysis of Aβ believed to represent key structures that produce cyto- oligomerization. Aβ oligomerization was assessed based on toxicity, contribute to synaptic deficits and initiate the the presence of high-molecular weight (HMW) oligomers detrimental cascade involved in the pathology of (>23 kDa) and low-molecular weight (LMW) oligomers AD [5, 7, 8]. Soluble Aβ oligomers are therefore (<23 kDa) [6, 21]. Results revealed that intra-hippocampal considered to be viable drug targets for the treatment Aβ injection produced a significant amount of oligomerized of AD [5, 9]. Aβ in the hippocampus, whereas Aβ in the NH4OH solution Galectin-3 (Gal-3) is a member of the galectin protein (without intra-hippocampal injection) exhibited formation family. The members of this large family of animal lec- of only 2-mer Aβ oligomers (Fig. 1a, b). These results tins interact with other proteins; the carbohydrate recog- demonstrated that the Aβ oligomers seen following exo- nition domain of a galectin recognizes a β-galactoside genous Aβ injection were formed in the brain rather than conjugate on the interacting protein [10], and this inter- being formed in the solution per se. action produces various biological effects [11]. Gal-3 is Next, we examined the level of Aβ oligomerization over present both inside the cell and within the extracellular time after intra-hippocampal Aβ injection. Results indicated space [12]. It exists in the monomer form under soluble that Aβ oligomerization exhibited a time-dependent condition and forms pentamers when bound to the increase in the mouse hippocampus following Aβ injec- β-galactose of an interacting protein [13]. This char- tion. This effect was first apparent at 48 h postinjection and acteristic allows Gal-3 to form bridges among cells it was most significant at 14 days postinjection (Fig. 1c, d). through its multiple binding to β-galactose on different The same results were also found in the rat hippocampus proteins. Gal-3 has been shown to regulate various cel- (Supplementary Fig. S1). lular functions. For example, Gal-3 was found to promote tumor progression [14]; contribute to cell–extracellular Aβ oligomerization is reduced in Gal-3 KO mice matrix adhesion [15]; and promote inflammatory injected with Aβ responses [16, 17]. The serum concentration of Gal-3 is increased in cancer patients, and Gal-3 enhances the Given that Gal-3 was previously shown to enhance cancer homotypic aggregation of cancer cells and enables them cell aggregation [18], we examined whether Gal-3 might to avoid anoikis by interacting with the cancer-associated also facilitate Aβ aggregation. Wild type (WT) and Gal-3 mucin protein, MUC1 [18]. We recently reported that KO mice received Aβ or NH4OH injection to their CA1 area water maze training and contextual fear conditioning and were sacrificed 48 h later. The dissected hippocampal training both decrease Gal-3 expression in the rat hip- tissues were subjected to Western blot analysis of Aβ oli- pocampus, and that memory performance is improved in gomerization and Gal-3 expression. We observed a light Gal-3-knockout (KO) mice [19]. In the context of the background signal and some inter-individual differences in present study, it is notable that the serum level of Gal-3 is the control group. Acute Aβ injection dramatically increased in AD patients [20]. Together, these findings increased both HMW and LMW Aβ oligomerization. The suggest that Gal-3 expression is negatively associated Aβ oligomerization level was also low in Gal-3 KO mice, with memory function under both physiological and which showed some inter-individual differences. Aβ oli- pathological conditions. However, although Gal-3 was gomerization was significantly lower in Gal-3 KO mice reported to enhance cancer cell aggregation [18], it was injected with Aβ compared to WT mice injected with Aβ previously unknown whether Gal-3 affects protein (Fig. 2a, b). Meanwhile, Aβ injection markedly increased aggregation in the brain and/or whether Gal-3 plays a role Gal-3 expression (Fig. 2a, c). in the pathology of AD. Here, we used APP/PS1 mice and Since Aβ oligomerization was reduced in Gal-3 KO mice brain tissues from AD patients to examine the role and injected with Aβ, we hypothesized that overexpression of action mechanism of Gal-3 in Aβ aggregation and amy- Gal-3 would facilitate Aβ oligomerization. To test this loid plaque formation. hypothesis, mice received different combinations of Aβ 194 C.-C. Tao et al. n io a hippocampus t lu ) o n s io ) t d H c O je 4 4 n 1 ) H i ( d N o H 4 n 1 n ( O ( i 4 β ly H β A n (kDa) N A o 180 135 100 b HMW LMW 75 ** 63 HMW 1.4 # 48 oligomer 1.2 35 1.0 IB: Aβ 0.8 25 0.6 20 5 mer 0.4 17 0.2 4 mer Optical density/Actin (fold) 0 3 mer H ta e ) 11 O ) b d 4 d H A 4 4 N (1 2 mer (1 5 Hippocampal 1 mer injection Actin c hippocampus d H 8h d 4 O 6h 4 8 1 (kDa) H 4 β β β β N A A A A 180 135 100 75 d 63 # 6 HMW LMW 48 HMW 5 oligomer # 35 4 IB: Aβ # 25 3 * # 20 5 mer 2 ** 17 4 mer 3 mer 1 Optical density/Actin (fold) 11 0 2 mer H h d O 6h 8 8 4d 4 β 4 β 1 5 H A β A β 1 mer N A A Actin (or NH4OH) and Flag-tagged plasmid injections.
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