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• Research Paper Volume 10, Issue 11 pp 3229-3248

  Methanolic extract of Tamarix Gallica attenuates hyperhomocysteinemia induced AD-like pathology and cognitive impairments in rats

  Relevance score: 8.784431

  Maibouge Tanko Mahamane Salissou, Yacoubou Abdoul Razak Mahaman, Feiqi Zhu, Fang Huang, Yuman Wang, Zhendong Xu, Dan Ke, Qun Wang, Rong Liu, Jian-Zhi Wang, Bin Zhang, Xiaochuan Wang

  Keywords: Alzheimer disease, Tamarix Gallica (TG), homocysteine, tau, Amyloid-β (Aβ), cognitive impairments

  Published in Aging on November 12, 2018

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  Although few drugs are available today for the management of Alzheimer’s disease (AD) and many plants and their extracts are extensively employed in animals’ studies and AD patients, yet no drug or plant extract is able to reverse AD symptoms adequately. In the present study, Tamarix gallica (TG), a naturally occurring plant known for its strong antioxidative, anti-inflammatory and anti-amyloidogenic properties, was evaluated on homocysteine (Hcy) induced AD-like pathology and cognitive impairments in rats. We found that TG attenuated Hcy-induced oxidative stress and memory deficits. TG also improved neurodegeneration and neuroinflammation by upregulating synaptic proteins such as PSD95 and synapsin 1 and downregulating inflammatory markers including CD68 and GFAP with concomitant decrease in proinflammatory mediators interlukin-1β (IL1β) and tumor necrosis factor α (TNFα). TG attenuated tau hyperphosphorylation at multiple AD-related sites through decreasing some kinases and increasing phosphatase activities. Moreover, TG rescued amyloid-β (Aβ) pathology through downregulating BACE1. Our data for the first time provide evidence that TG attenuates Hcy-induced AD-like pathological changes and cognitive impairments, making TG a promising candidate for the treatment of AD-associated pathological changes.

  

  TG treatment improved Hcy-induced learning and spatial memory impairments. Sixty male SD rats were divided into 5 groups as Control, Homocysteine only (HHcy), Low TG treatment (Low TG), High TG treatment (High TG) and Positive Control (SCR1693) groups. The rats were subjected to 3 trials per day to find the hidden platform in the Morris Water Maze (MWM) and the memory and learning abilities of the animals were tested for 60s on the seventh day. (A) Escape latency to find the hidden platform in MWM for the six training days. (B) First crossing latency and (C) mean number of crossing the position of the hidden platform on the test day. (D) Time spent and (E) distance traveled in the target quadrant on the test day. (F) Average speed during the 60s of the test. HHcy rats showed impaired spatial learning and memory and treatment with either low or high TG rescued these impairments. The data were expressed as mean ± SEM (n = 12). # P < 0.05, ## P < 0.01, ### P < 0.001, #### P < 0.0001 versus control and * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 versus HHcy.

  
  
  

  

  TG attenuated Hcy-induced oxidative stress. (A) Relative SOD activity and (B) relative level of MDA in serum. Compared with control group, HHcy rats showed decreased activity of SOD and increased level of MDA. Both treatment high and low with TG markedly increased SOD activity and decreased MDA level. The data were expressed as mean ± SEM. Data were from 3 different animals in each group (n = 3). ### P < 0.001 versus control; ** P < 0.01, *** P < 0.001 versus HHcy.

  
  
  

  

  Supplementation with TG recovered dendritic spine and neuronal loss. After two weeks of Hcy (400 µg/kg/day) and two weeks TG treatment post-injection, the rats were sacrificed following behavioral test. (A and B) Representative Nissl staining images and the quantification of neuronal density, chart bar = 500 and 100 µm for low and high magnifications respectively. (C and D) Representative Golgi staining images and quantification of dendritic spines from randomly selected dendritic segments of randomly selected hippocampal neurons, chat bar = 5µm. HHcy animals showed neurodegeneration which was recovered following supplementation with both low and high TG doses. The data were expressed as mean ± SEM and n = 3 for both Nissl and Golgi staining. ### P < 0.001 versus control; ** P < 0.01, *** P < 0.001 versus HHcy.

  
  
  

  

  TG supplementation attenuated the decrease of memory-related proteins. (A) Levels of synapsin 1 and PSD95 were detected using western blotting technique in the hippocampus and β-actin was used as loading control. (B and C) Quantitative analysis of the blots showed that Hcy dramatically decreased the expression of these synaptic proteins in the hippocampus when compared with control group, and treatment with TG reversed these effects. The data were expressed as mean ± SEM (n = 6). # P < 0.05, ## P < 0.01 versus control; * P < 0.05, ** P < 0.01 versus HHcy.

  
  
  

  

  TG downregulated neuroinflammation induced by Hcy injection in rats. (A-C) Western blots and quantitative analysis of inflammatory markers CD68 and GFAP (n = 6). TG treatment decreased the Hcy-upregulated level of these markers back to control level. (D and E) ELISA results revealed an increased level of inflammatory mediators TNFα and IL1β following Hcy injection and a decrease upon TG supplementation (n = 3). The data were expressed as mean ± SEM. # P < 0.05, ## P < 0.01, ### P < 0.001, #### P < 0.0001 versus control and * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 versus HHcy.

  
  
  

  

  Treatment with TG mitigated Hcy-induced tau hyperphosphorylation. (A) Phosphorylation status of tau protein as measured by Western blotting in the hippocampus after Hcy treatment and TG supplementation. (B) Total tau (Tau5) normalized to β-actin. (C-E) Quantitative analysis of the blots of phosphorylated tau probed with several phosphorylated-tau antibodies normalized to total tau (Tau5). A significant decrease in tau hyperphosphorylation at several studied sites was seen following TG administration. The data were expressed as mean ± SEM (n = 6). ## P < 0.01, ### P <0.001 versus control; * P < 0.05, ** P < 0.01, *** P < 0.001 versus HHcy.

  
  
  

  

  TG decreased the phosphorylation level of tau by modulated tau related phosphatase and kinases. (A-D) Western blotting and quantitative analysis of total glucose synthase kinase 3β (GSK3β), phosphorylated GSK3β at Ser9 (GSK3β-pS9) and total protein phosphatase 2A (PP2A) (n = 6). No significant difference in the total level of either GSK3β or PP2A among all groups, but the GSK3β-pS9 was significantly high in HHcy and was reduced following TG supplementation. GSK3β (E) and PP2A (F) activity tests (n = 3) revealed an increased GSK3β and a decreased PP2A activity after Hcy which were reversed by both low and high TG treatments. The data were expressed as mean ± SEM. # P < 0.05, ## P < 0.01, #### P <0.0001 versus control; * P < 0.05, ** P < 0.01, **** P < 0.0001 versus HHcy.

  
  
  

  

  TG decreased tau hyperphosphorylation by decreasing the activity of tau related Ca²⁺-dependent kinases CDK5 and CaMKII. (A) Western blots of total Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), phosphorylated CaMKII at Thr286 (CaMKII-pT286), total cyclin dependent kinase 5 (CDK5) and CDK5 activators (p35 and p25) in the hippocampal lysates. (B-F) Quantitative analysis of the blots, total CaMKII, CDK5, p35 and p25 were normalized to β-actin while CaMKII-pT286 was normalized to total CaMKII. (G) The ratio of p25/p35. Total protein levels of CaMKII and CDK5 were comparable among all groups, however their activities, as measured by increased CaMKII-pT286 for CaMKII and increase in both activators (p25 & p35) and ratio of p25/p35 for CDK5, were high in HHcy group and decrease to control level by TG treatment. The data were expressed as mean ± SEM (n = 6). # P < 0.05, ## P < 0.01, ### P < 0.001, #### P < 0.0001 versus control; ** P < 0.01, *** P < 0.001, **** P < 0.0001 versus HHcy.

  
  
  

  

  Supplementation with TG attenuated Hcy-induced Aβ pathology. (A) Levels of total amyloid precursor protein (APP), the β APP cleaving enzyme 1 (BACE1) cleaved APP [APPβ] and the total BACE1 were estimated by western blot (n = 6). (B-D) Quantification of the western blot results with APP and BACE1 normalized to β-actin and APPβ normalized to total APP. Total APP level remained unchanged, however the APPβ and BACE1 were high in the HHcy group while they were similar to control in the TG treatments groups. (E) ELISA assay for Aβ_1-42 (n = 3) with significantly low levels of Aβ_1-42 in the control, positive control and TG groups compared to level found in the HHcy group. The data were expressed as mean ± SEM. # P < 0.05, ## P < 0.01, ### P < 0.001 versus control; * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 versus HHcy.