臺灣博碩士論文加值系統

阿茲海默症是最常見導致失智的疾病，其病理特徵為乙型類澱粉蛋白形成老年斑塊沉積於大腦中。阿茲海默症與代謝性壓力密切相關，高血糖會促進乙型類澱粉蛋白形成並在斑塊並在附近造成膠細胞過度活化。與正常人相比，在阿茲海默症患者身上對於乙型類澱粉蛋白生成速度並無差異，但清除能力則有顯著障礙，因而導致乙型類澱粉蛋白過度沉積，但高糖是否會對神經膠細胞 清除及代謝乙型類澱粉蛋白功能產生影響並不得知。本研究使用初代混合膠細胞培養方法探討持續性高糖是否會造成清除能及代謝之差異。在正常小鼠腦中，微型膠細胞為不活化狀態。但在單獨培養時會活化改變型態並分泌細胞激素。當微型膠細胞與星狀細胞共同培養時，微型膠細胞並不會活化及分泌細胞激素。由於混合膠細胞培養的反應比較接近正常腦部的狀態，本研究使用混合膠細胞培養於高糖(25mM；模擬高血糖狀態)及正常糖 (5.5mM)中共16天後，加入螢光標示乙型類澱粉蛋白觀察內吞及代謝能力。研究發現在星狀細胞在一小時穩定狀態下內吞能力，受到高糖影響而減弱。微型膠細胞在5-15分鐘後受高糖影響，但是在一小時後總內吞則不受高糖的作用。雖然乙型類澱粉蛋白從早期內吞體到溶酶體的運輸過程，並未受到高糖的影響。不過，星狀細胞及微型膠細胞對於乙型類澱粉蛋白分解能力，則因高糖影響而速度減慢。進一步分析溶酶體功能方面（溶酶體酸化與水解酶活性），高糖會抑制酸化程度及酵素水解功能。另外高糖也會降低粒線體膜電位，可能對膠細胞清除及代謝能力造成影響，進而造成乙型類澱粉蛋白沉積。為了進一步了解，細胞模型所觀測的現象，是否可以在現於模式動物。本研究運用有代謝性壓力APP/PS1基因轉殖鼠，觀察高血糖等代謝壓力，對於乙型類澱粉蛋白沉積與神經退化的影響。另外，黃耆多醣體目前廣泛用於中藥治療，具有改善高血糖及胰島素抗性。本研究運用黃耆多醣體於上，代謝性壓力APP/PS1基因轉殖鼠，了解緩解代謝壓力後，是否能緩解阿茲海默病症惡化。作為開發藥物治療阿茲海默症。APP/PS1基因轉殖鼠小鼠上給予餵養高脂肪餐及施打streptozotocin產生代謝性壓力，在14周大時給予口服黃耆多醣體共7週。研究發現黃耆多醣體可改善高血糖高血脂的APP/PS1基因轉殖鼠胰島素抗性、三酸甘油脂及葡萄糖耐受性及降低體重，但血糖濃度僅在服用後前三周有部分改善。在大腦組織切片中發現，代謝壓力提前增加乙型類澱粉蛋白沉積斑塊，與周圍星狀細胞及微型膠細胞活化。黃耆多醣體可以減緩斑塊周圍星狀細胞及微型膠細胞活化，但斑塊數量則不受影響。在認知功能方面，黃耆多醣體減緩代謝壓力所造成的AD小鼠的過長築巢時間。黃耆多醣體可能經由減輕高血脂造成的代謝性壓力與神經發炎程度，進而改善認知功能。
總結本研究的主要的貢獻，運用混合膠細胞培養，解析長時間高糖對乙型類澱粉蛋白分解與乙型類澱粉蛋白對於神經膠細胞活化的影響。此一新型細胞模式所觀察到高糖增加乙型類澱粉蛋白累積與乙型類澱粉蛋白累積引發神經膠細胞活化現象，可以再現於高血脂及高血糖造成的代謝性壓力模式小鼠（乙型類澱粉蛋白累積增加而且神經膠細胞活化指出現於累積位置）。透過黃耆多醣體減輕血脂但是對長期血糖的作用並無減輕，以及其對乙型類澱粉蛋白清除並無影響來看，間接驗證抑制乙型類澱粉蛋白累積可能是高血糖或者高血脂與高血糖的協同作用。根據上述結果，相較於純神經膠細胞培養與短時間高糖刺激，混合神經膠細胞培養比較接近腦中的生理與代謝壓力造成神經退化的病理狀態。由於細胞模型易於快速解析分子機制的優越性，本研究透過此一新型細胞模式，了解高糖對降解乙型類澱粉蛋白胞器的抑制，主要對溶酶體的功能與酸化抑制，而非影響乙型類澱粉蛋白的內膜運輸。

Alzheimer’s disease (AD) is the most prevalent cause of dementia. Pathological characteristic of AD is deposition of senile plaques consisting of beta-amyloid (Aβ) peptides in the cerebrum. AD is highly associated with metabolic stress, e.g. hyperglycemia exacerbates Aβ burden and glia activation around plaques. In sporadic AD patients, instead of cerebral Aβ biogenesis, disorders of Aβ clearance and degradation result in more Aβ accumulation and leading to cognitive disorders. It is unclear how hyperglycemia inhibit degradation of Aβ. This study has combined a better cell model and metabolically-stressed AD animal model to dissect the effects of sustained high glucose on the clearance of Aβ. In normal mouse brains, microglia are in resting state. However, microglia activation was observed in pure microglia cultures according to their cytokine expression and morphology. Astrocyte and microglia mixed culture seems to be a better model for this study because cytokine levels were undetectable and microglia morphology remained in ramified which are similar to resting normal brains. Mixed glia cultured in high glucose (HG = 25 mM; to mimic hyperglycemia) and normal glucose (NG = 5.5 mM) media for 16 days were applied to dissect effects of sustained hyperglycemia on clearance and degradation of Aβ. Fluorescent labeled oAβ was used for visualization of Aβ uptake and degradation. 1-hr steady state uptake of Aβ was inhibited in astrocytes and microglia after 5-15min HG treatment. 1-hr steady state uptake of Aβ was similar in microglia after treatments of HG and NG but it was still reduced in astrocytes in HG. The degradation rate in astrocytes was decreased after 1-hr chase in HG. In microglia, degradation of Aβ was only decreased after 15 min chase in HG. HG had no effect on Aβ trafficking from endosomes to lysosomes. To evaluate effects of HG on lysosomal activity, lysosensor dye and DQ-BSA were used to test for acidification and hydrolysis. In HG, fluorescence intensity of lysosensor and DQ-BSA were attenuated in astrocytes and microglia. Previous investigations showed that acute hyperglycemia resulted in mitochondrial dysfunction. Sustained HG also affected mitochondrial membrane potential to induce defects in Aβ clearance and degradation. In summary, sustained HG reduces lysosomal activity instead of trafficking of Aβ to inhibit degradation of Aβ. Although sustained HG inhibits mitochondrial membrane potential, it is still unclear whether such mitochondrial dysfunctions affects lysosomal activity. According to cell-based results, this study further investigated whether such phenomena can be reproduced in diabetic AD mouse model and rescued by Astragalus membranaceus(APS) which improves hyperglycemia and insulin resistance through regulation the insulin signal. APP/PS1transgenic mice were administrated high-fat diet and injecting of low-dose streptozotocin to induce metabolically stressed AD mice prior to the appearance of senile plaques. APS was administrated starting at 14 weeks for 7 weeks. APS reduced metabolic stress-induced body weight increase, insulin and leptin level, insulin resistance, and triglyceride level. In brain sections of AD mice, metabolic stress-elicited astrocytes and microglia activation in the vicinity of plaques was enhanced by metabolic stress and diminished by APS administration. Nesting behavior is inhibited by metabolic stress and improved after APS administration in AD mice. These findings suggest that metabolic stress-induced hyperglycemia worsened AD progression and APS ameliorate metabolic stress-induced hyperglycemia, hyperlipidemia and the subsequent neuroinflammation, the behavior performance in metabolically-stressed AD mice. In summary, metabolic stress induces more severe Aβ accumulation early and such progression was reduced by improving metabolic status via APS treatment. The mixed glia cultures are better cell-based system to dissect intracellular details induced by Aβ.

Contents………………………………………………………………………………i
List of figures………………………………………………………………………iv
Chinese Abstract……………………………………………………………………v
English Abstract…………………………………………………………………… vii
Introduction…………………………………………………………………………1
Alzheimer’s disease and pathology in brain…………………………………………1
The mechanism of Aβ internalization and degradation by neurons and glia…………2
The mechanism how increase of Aβ activates glia to cause neuronal cell death………3
Diabetes and AD………………………………………………………………………5
Hyperglycemia worse lysosomal and mitochondrial functions………………………6
Current pharmacologic treatments for AD……………………………………………7
Current AD models for studies in etiology and drug screen……………………………8
The Goal of this study…………………………………………………………10
Materials and methods……………………………………………………………12
Mixed astrocytes and microglia culture………………………………………………12
FAM labeled A preparation……………………………………………………12
Cytokine expression level……………………………………………………………12
Endosome and Lysosome immunostaining…….……………………………………13
Immunocytochemistry of mixed glia cells……………………………………………13
Lysosome acidification assessment…………………………………………………14
Lysosomal hydrolysis activity assay…………………………………………………14
JC-10 mitochondria membrane potential assay………………………………………14
Colocalization test……………………………………………………………………15
Confocal microscopy…………………………………………………………………15
Isolation of Polysaccharides…………………………………………………………15
Size-Exclusion Chromatography (SEC)……………………………………………16
Hydrolysis and Monosaccharides Compositional Determination of the Polysaccharide………………………………………………………………………16
Animal Management and Administration……………………………………………17
Metabolic Stress Induction………………………………………………………17
Tissue Sample Collection…………………………………………………………….18
Measurement of Aβ…………………………………………………………………18
Senile Plaques Staining and Immunohistochemistry…………………………18
Plaque Quantification…………………………………………………………19
Quantification of GFAP Intensity Surrounding Plaque and Plaque-Associated Iba-1 Intensity…………………………………………………………19
Nesting Behavior……………………………………………………………………20
Statistical Analysis………………………………………………………………20
Results………………………………………………………………………………21
Primary microglia cultures instead mixed glial cultures were activated in both normal and high glucose media…………………21
Comparison of the effect of HG on uptake of oAβ by astrocytes and microglia in mixed glial cultures after administrating oAβ…………………………………22
HG reduced degradation of Aβ by astrocytes and microglia in mixed glial cultures……………………………………………………………………………….23
HG has no effect on Aβ trafficking from early endosome to lysosome…………24
HG reduced lysosomal acidification and hydrolysis activity………………………24
HG resulted in lower mitochondrial membrane potential……………………………25
The mRNA levels of SR-B receptor were down-regulated in HG……………………26
Characterization of Astragalus membranaceus Polysaccharides (APS)………………26
APS did not Significantly Reduce HFSTZ-Aggravated Cerebral Aβ Deposition.........27
APS did not Significantly decrease HFSTZ-aggravated cerebral and serum Aβ level…………………………………………………………………………………27
APS Diminished HFSTZ-Activated Plaque-Associated Astrocytes and Microglia…27
APS Ameliorated HFSTZ-Prolonged Time for Nest Construction in AD Mice………28
Discussion……………………………………………………………………………30
Mixed glial cultures show more pathological and physiological characteristics than pure glial cultures……………………………………………………………………30
Astrocytes and microglia have different kinetics and capacity of internalization Aβ and responses to sustained high glucose…………………………………………………32
High glucose reduces Aβ degradation via inhibiting lysosomal acidification and lytic activity instead trafficking to lysosomes……………………………………………33
Possible mechanisms may explain HG-attenuated lysosomal activity………………34
APS reduce fatty acid and insulin resistance instead blood glucose in metabolically stressed AD mice……………………………………………36
APS has no effects on plasma Aβ clearance by liver or BBB in mouse model……37
APS has reduced glial activation but no effects on clearance of plagues in metabolically stressed mouse brains……………………38
APS improve nesting speed via reducing glial activation instead clearance of amyloid plagues……………………………………………………40
Conclusions…………………………………………………………………………41
References…………………………………………………………………………42
List of figures
Figure 1. Comparison of effects of HG on activation of pure microglia and mixed glial cultures.……………………………………………………58
Figure 2. HG mixed glia culture did not change microglia/astrocyte cell ratio……60
Figure 3. HG has no effect on nuclear morphology of mixed glial cultures..……...…..61
Figure 4. Comparison of the effect of HG on uptake of oAβ by astrocytes and microglia in mixed glial cultures after administrating oAβ for 1hr.……………………….……..63
Figure 5. Comparison of the effect of HG on uptake of oAβ by astrocytes and microglia in mixed glial cultures after administrating oAβ for 5 and 15 mins…………….……65
Figure 6. The degradation of Aβ by astrocytes and microglia was attenuated in HG….67
Figure 7. HG has no effect on Aβ trafficking from endosome to lysosome…………...70
Figure 8. Lysosomal acidification was attenuated in glial cells by sustained HG……74
Figure 9. Lysosomal hydrolysis capacity was attenuated in glia cells after sustained HG treatment……………………………………………………………………………...77
Figure 10. HG resulted in lower mitochondria membrane potential…………………..79
Figure 11. The mRNA levels of SR-B receptor was down-regulated in HG…………..81
Figure 12 . The composition of Astragalus membranaceus Polysaccharides………….82
Figure 13. Schematic diagram of the experimental paradigm………………………83
Figure 14. APS did not ameliorate HFSTZ-aggravated cerebral plague burden………84
Figure 15. APS did not decrease cerebral and serum A level………………………...86
Figure 16. APS ameliorated HFSTZ-augmented activation of astrocytes in the vicinity of plaques……………………………………………………………………………..87
Figure17. APS ameliorated HFSTZ-augmented activation of plaques-associated microglia……………………………………………………………………………...90
Figure 18. APS improved HFSTZ-prolonged nesting construction time…………….92

Adolfsson, O., Pihlgren, M., Toni, N., Varisco, Y., Buccarello, A. L., Antoniello, K., Atwal, J. K. (2012). An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. Journal of Neuroscience, 32(28), 9677-9689.

Allaman, I., Belanger, M., & Magistretti, P. J. (2011). Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci, 34(2), 76-87. doi:10.1016/j.tins.2010.12.001

Ascaso, J. F., Pardo, S., Real, J. T., Lorente, R. I., Priego, A., & Carmena, R. (2003). Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism. Diabetes care, 26(12), 3320-3325.

Ard, M. D., Cole, G. M., Wei, J., Mehrle, A. P., & Fratkin, J. D. (1996). Scavenging of Alzheimer's amyloid β‐protein by microglia in culture. Journal of neuroscience research, 43(2), 190-202

Baik, S. H., Kang, S., Lee, W., Choi, H., Chung, S., Kim, J.-I., & Mook-Jung, I. (2019). A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease. Cell Metabolism.

Baik, S. H., Kang, S., Son, S. M., & Mook-Jung, I. (2016). Microglia contributes to plaque growth by cell death due to uptake of amyloid beta in the brain of Alzheimer's disease mouse model. Glia, 64(12), 2274-2290. doi:10.1002/glia.23074

Ballabio, A., & Bonifacino, J. S. (2019). Lysosomes as dynamic regulators of cell and organismal homeostasis. Nature reviews Molecular cell biology, 1-18.

Basak, J. M., Verghese, P. B., Yoon, H., Kim, J., & Holtzman, D. M. (2012). Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Aβ uptake and degradation by astrocytes. Journal of Biological Chemistry, 287(17), 13959-13971.

Bernstein, H.-G., Lendeckel, U., Bukowska, A., Ansorge, S., Ernst, T., Stauch, R., Bogerts, B. (2008). Regional and cellular distribution patterns of insulin-degrading enzyme in the adult human brain and pituitary. Journal of chemical neuroanatomy, 35(2), 216-224.

Billings, L. M., Oddo, S., Green, K. N., McGaugh, J. L., & LaFerla, F. M. (2005). Intraneuronal Aβ causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron, 45(5), 675-688.

Block, M. L., Zecca, L., & Hong, J. S. (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci, 8(1), 57-69. doi:10.1038/nrn2038

Bloom, G. S. (2014). Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol, 71(4), 505-508. doi:10.1001/jamaneurol.2013.5847

Bronzuoli, M. R., Iacomino, A., Steardo, L., & Scuderi, C. (2016). Targeting neuroinflammation in Alzheimer’s disease. Journal of inflammation research, 9, 199.
Cai, Z., Hussain, M. D., & Yan, L.-J. (2014). Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer's disease. International Journal of Neuroscience, 124(5), 307-321.

Cang, C., Zhou, Y., Navarro, B., Seo, Y.-j., Aranda, K., Shi, L., Ren, D. (2013). mTOR regulates lysosomal ATP-sensitive two-pore Na+ channels to adapt to metabolic state. Cell, 152(4), 778-790.

Carpenter, A. E., Jones, T. R., Lamprecht, M. R., Clarke, C., Kang, I. H., Friman, O., Moffat, J. (2006). CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome biology, 7(10), R100.

Castellano, J. M., Guinda, A., Delgado, T., Rada, M., & Cayuela, J. A. (2013). Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes. Diabetes, 62(6), 1791-1799.

Cherbuin, N., Sachdev, P., & Anstey, K. J. (2012). Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study. Neurology, 79(10), 1019-1026.

Chiang, M.-C., Nicol, C. J., & Cheng, Y.-C. (2018). Resveratrol activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced inflammation and oxidative stress. Neurochemistry international, 115, 1-10.

Chyung, J. H., & Selkoe, D. J. (2003). Inhibition of receptor-mediated endocytosis demonstrates generation of amyloid β-protein at the cell surface. Journal of Biological Chemistry, 278(51), 51035-51043.

Colacurcio, D. J., & Nixon, R. A. (2016). Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease. Ageing research reviews, 32, 75-88.

Coughlan, K. A., Valentine, R. J., Ruderman, N. B., & Saha, A. K. (2014). AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes, 7, 241-253. doi:10.2147/DMSO.S43731

Cras, P., Kawai, M., Lowery, D., Gonzalez-Dewhitt, P., Greenberg, B., & Perry, G. (1991). Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein. Proceedings of the National Academy of Sciences, 88(17), 7552-7556.

Crews, L., & Masliah, E. (2010). Molecular mechanisms of neurodegeneration in Alzheimer's disease. Hum Mol Genet, 19(R1), R12-20. doi:10.1093/hmg/ddq160

Cusack, C. L., Swahari, V., Henley, W. H., Ramsey, J. M., & Deshmukh, M. (2013). Distinct pathways mediate axon degeneration during apoptosis and axon-specific pruning. Nature communications, 4, 1876.

Daulatzai, M. A. (2017). Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J Neurosci Res, 95(4), 943-972. doi:10.1002/jnr.23777

de la Monte, S. M. (2014). Type 3 diabetes is sporadic Alzheimers disease: mini-review. Eur Neuropsychopharmacol, 24(12), 1954-1960. doi:10.1016/j.euroneuro.2014.06.008

Deacon, R. M. (2006). Housing, husbandry and handling of rodents for behavioral experiments. Nat Protoc, 1(2), 936-946. doi:10.1038/nprot.2006.120

Deacon, R. M., Croucher, A., & Rawlins, J. N. (2002). Hippocampal cytotoxic lesion effects on species-typical behaviours in mice. Behav Brain Res, 132(2), 203-213.

Doens, D., & Fernández, P. L. (2014). Microglia receptors and their implications in the response to amyloid β for Alzheimer’s disease pathogenesis. Journal of neuroinflammation, 11(1), 48.

Dun, C., Liu, J., Qiu, F., Wu, X., Wang, Y., Zhao, Y., & Gu, P. (2016). Effects of Astragalus polysaccharides on memory impairment in a diabetic rat model. Neuropsychiatr Dis Treat, 12, 1617-1621. doi:10.2147/ndt.S106123

Eckel, R. H., Alberti, K., Grundy, S. M., & Zimmet, P. Z. (2010). The metabolic syndrome. The Lancet, 375(9710), 181-183.

English, J. A., Harauma, A., Föcking, M., Wynne, K., Scaife, C., Cagney, G., Cotter, D. R. (2013). Omega-3 fatty acid deficiency disrupts endocytosis, neuritogenesis, and mitochondrial protein pathways in the mouse hippocampus. Frontiers in genetics, 4, 208.

Fang, Y., Wang, J., Yao, L., Li, C., Wang, J., Liu, Y., Liao, H. (2018). The adhesion and migration of microglia to β-amyloid (Aβ) is decreased with aging and inhibited by Nogo/NgR pathway. Journal of neuroinflammation, 15(1), 210.

Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., Guénette, S. (2003). Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proceedings of the National Academy of Sciences, 100(7), 4162-4167.

Flannagan, R. S., Jaumouillé, V., & Grinstein, S. (2012). The cell biology of phagocytosis. Annual Review of Pathology: Mechanisms of Disease, 7, 61-98.
Forgac, M. (2007). Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nature reviews Molecular cell biology, 8(11), 917.

Fukasawa, M., Nishijima, M., & Hanada, K. (1999). Genetic evidence for ATP-dependent endoplasmic reticulum-to-Golgi apparatus trafficking of ceramide for sphingomyelin synthesis in Chinese hamster ovary cells. The Journal of cell biology, 144(4), 673-685.

Furman, J. L., Sama, D. M., Gant, J. C., Beckett, T. L., Murphy, M. P., Bachstetter, A. D., Norris, C. M. (2012). Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer's disease. J Neurosci, 32(46), 16129-16140. doi:10.1523/jneurosci.2323-12.2012

Fuster, D. G., & Alexander, R. T. (2014). Traditional and emerging roles for the SLC9 Na+/H+ exchangers. Pflügers Archiv-European Journal of Physiology, 466(1), 61-76.

Gali, C. C., Fanaee-Danesh, E., Zandl-Lang, M., Albrecher, N. M., Tam-Amersdorfer, C., Stracke, A., Avdili, A. (2019). Amyloid-beta impairs insulin signaling by accelerating autophagy-lysosomal degradation of LRP-1 and IR-β in blood-brain barrier endothelial cells in vitro and in 3XTg-AD mice. Molecular and Cellular Neuroscience, 99, 103390.

Gantman, A., Fuhrman, B., Aviram, M., and Hayek, T. (2010). High glucose stimulates macrophage SR-BI expression and induces a switch in its activity from cholesterol efflux to cholesterol influx. Biochem. Biophys. Res. Commun. 391, 523–528.

Garwood, C. J., Ratcliffe, L. E., Morgan, S. V., Simpson, J. E., Owens, H., Vazquez-Villaseñor, I., .Wharton, S. B. (2015). Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors. Molecular brain, 8(1), 51.

Gruetter, R., Ugurbil, K., & Seaquist, E. R. (1998). Steady‐state cerebral glucose concentrations and transport in the human brain. Journal of neurochemistry, 70(1), 397-408.

Hamilton, A., & Holscher, C. (2012). The effect of ageing on neurogenesis and oxidative stress in the APPswe/PS1deltaE9 mouse model of Alzheimer's disease. Brain research, 1449, 83-93.

Han, R., Tang, F., Lu, M., Xu, C., Hu, J., Mei, M., & Wang, H. (2016). Protective effects of Astragalus polysaccharides against endothelial dysfunction in hypertrophic rats induced by isoproterenol. Int Immunopharmacol, 38, 306-312. doi:10.1016/j.intimp.2016.06.014

Hasegawa, J., Iwamoto, R., Otomo, T., Nezu, A., Hamasaki, M., & Yoshimori, T. (2016). Autophagosome–lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome. The EMBO journal, 35(17), 1853-1867.

Hayek, S. R., Rane, H., & Parra, K. J. (2019). Reciprocal Regulation of V-ATPase and Glycolytic Pathway Elements in Health and Disease. Frontiers in physiology, 10, 127.

He, X., Shu, J., Xu, L., Lu, C., & Lu, A. (2012). Inhibitory effect of Astragalus polysaccharides on lipopolysaccharide-induced TNF-a and IL-1beta production in THP-1 cells. Molecules, 17(3), 3155-3164. doi:10.3390/molecules17033155

Hickman, S. E., Allison, E. K., & El Khoury, J. (2008). Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice. Journal of Neuroscience, 28(33), 8354-8360.

Huang, W. M., Liang, Y. Q., Tang, L. J., Ding, Y., & Wang, X. H. (2013). Antioxidant and anti-inflammatory effects of Astragalus polysaccharide on EA.hy926 cells. Exp Ther Med, 6(1), 199-203. doi:10.3892/etm.2013.1074

Huang, Y.-C., Tsay, H.-J., Lu, M.-K., Lin, C.-H., Yeh, C.-W., Liu, H.-K., & Shiao, Y.-J. (2017). Astragalus membranaceus-polysaccharides ameliorates obesity, hepatic steatosis, neuroinflammation and cognition impairment without affecting amyloid deposition in metabolically stressed APPswe/PS1dE9 mice. Int J Mol Sci, 18(12), 2746.

Hurtado-Lorenzo, A., Skinner, M., El Annan, J., Futai, M., Sun-Wada, G.-H., Bourgoin, S., Ausiello, D. A. (2006). V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nature cell biology, 8(2), 124.

Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C., ... & Carson, C. T. (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature, 482(7384), 216-220.)

Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S., & Selkoe, D. (1989). Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol, 24(3), 173-182.

Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Borchelt, D. R. (2004). Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet, 13(2), 159-170. doi:10.1093/hmg/ddh019

Jiang, J. B., Qiu, J. D., Yang, L. H., He, J. P., Smith, G. W., & Li, H. Q. (2010). Therapeutic effects of astragalus polysaccharides on inflammation and synovial apoptosis in rats with adjuvant-induced arthritis. Int J Rheum Dis, 13(4), 396-405. doi:10.1111/j.1756-185X.2010.01555.x

Jin, M., Zhao, K., Huang, Q., & Shang, P. (2014). Structural features and biological activities of the polysaccharides from Astragalus membranaceus. Int J Biol Macromol, 64, 257-266. doi:10.1016/j.ijbiomac.2013.12.002

Jones, R. S., Minogue, A. M., Connor, T. J., & Lynch, M. A. (2013). Amyloid-β-induced astrocytic phagocytosis is mediated by CD36, CD47 and RAGE. Journal of Neuroimmune Pharmacology, 8(1), 301-311.

Kaksonen, M., & Roux, A. (2018). Mechanisms of clathrin-mediated endocytosis. Nature reviews Molecular cell biology, 19(5), 313.

Kandimalla, R., Thirumala, V., & Reddy, P. H. (2017). Is Alzheimer's disease a type 3 diabetes? A critical appraisal. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1863(5), 1078-1089.

Kanekiyo, T., & Bu, G. (2014). The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease. Frontiers in aging neuroscience, 6, 93.

Kim, J. A., Wei, Y., & Sowers, J. R. (2008). Role of mitochondrial dysfunction in insulin resistance. Circulation research, 102(4), 401-414.

Kim, J., Basak, J. M., & Holtzman, D. M. (2009). The role of apolipoprotein E in Alzheimer's disease. Neuron, 63(3), 287-303.

Kluve‐Beckerman, B., Manaloor, J. J., & Liepnieks, J. J. (2002). A pulse‐chase study tracking the conversion of macrophage‐endocytosed serum amyloid A into extracellular amyloid. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, 46(7), 1905-1913.

Kuhnke, D., Jedlitschky, G., Grube, M., Krohn, M., Jucker, M., Mosyagin, I., Warzok, R. W. (2007). MDR1‐P‐Glycoprotein (ABCB1) Mediates Transport of Alzheimer’s Amyloid‐β Peptides—Implications for the Mechanisms of Aβ Clearance at the Blood–Brain Barrier. Brain Pathology, 17(4), 347-353.

Kumar, A., & Singh, A. (2015). A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacological reports, 67(2), 195-203.

Levin, R., Grinstein, S., & Schlam, D. (2015). Phosphoinositides in phagocytosis and macropinocytosis. Biochimica Et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1851(6), 805-823.

Li, H.-q., Chen, C., Dou, Y., Wu, H.-j., Liu, Y.-j., Lou, H.-F., Duan, S. (2013). P2Y4 receptor-mediated pinocytosis contributes to amyloid beta-induced self-uptake by microglia. Molecular and cellular biology, 33(21), 4282-4293.

Li, J., Kanekiyo, T., Shinohara, M., Zhang, Y., LaDu, M. J., Xu, H., & Bu, G. (2012). Differential regulation of amyloid-β endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. Journal of Biological Chemistry, 287(53), 44593-44601.

Li, X. T., Zhang, Y. K., Kuang, H. X., Jin, F. X., Liu, D. W., Gao, M. B., Xin, X. J. (2012). Mitochondrial protection and anti-aging activity of Astragalus polysaccharides and their potential mechanism. Int J Mol Sci, 13(2), 1747-1761. doi:10.3390/ijms13021747

Liu, C.-C., Hu, J., Zhao, N., Wang, J., Wang, N., Cirrito, J. R., Bu, G. (2017). Astrocytic LRP1 mediates brain Aβ clearance and impacts amyloid deposition. Journal of Neuroscience, 37(15), 4023-4031.

Liu, J., Zhang, J. F., Lu, J. Z., Zhang, D. L., Li, K., Su, K., Ou-Yang, J. P. (2013). Astragalus polysaccharide stimulates glucose uptake in L6 myotubes through AMPK activation and AS160/TBC1D4 phosphorylation. Acta Pharmacol Sin, 34(1), 137-145. doi:10.1038/aps.2012.133

Liu, L., Chen, S., Xu, X., Hou, B., & Mo, F. (2017). Astragalus polysaccharides combined with ibuprofen exhibit a therapeutic effect on septic rats via an anti-inflammatory cholinergic pathway. Exp Ther Med, 14(4), 3127-3130. doi:10.3892/etm.2017.4865

Liu, M., Wu, K., Mao, X., Wu, Y., & Ouyang, J. (2010). Astragalus polysaccharide improves insulin sensitivity in KKAy mice: regulation of PKB/GLUT4 signaling in skeletal muscle. J Ethnopharmacol, 127(1), 32-37. doi:10.1016/j.jep.2009.09.055

Liu, M., Wu, K., Mao, X., Wu, Y., & Ouyang, J. (2010). Astragalus polysaccharide improves insulin sensitivity in KKAy mice: regulation of PKB/GLUT4 signaling in skeletal muscle. Journal of Ethnopharmacology, 127(1), 32-37.

Livingston, G., Sommerlad, A., Orgeta, V., Costafreda, S. G., Huntley, J., Ames, D., Cohen-Mansfield, J. (2017). Dementia prevention, intervention, and care. The Lancet, 390(10113), 2673-2734.

Lu, J., Chen, X., Zhang, Y., Xu, J., Zhang, L., Li, Z., He, X. (2013). Astragalus polysaccharide induces anti-inflammatory effects dependent on AMPK activity in palmitate-treated RAW264.7 cells. Int J Mol Med, 31(6), 1463-1470. doi:10.3892/ijmm.2013.1335

Luzio, J. P., Hackmann, Y., Dieckmann, N. M., & Griffiths, G. M. (2014). The biogenesis of lysosomes and lysosome-related organelles. Cold Spring Harb Perspect Biol, 6(9), a016840.

Ly, J. D., Grubb, D. R., & Lawen, A. (2003). The mitochondrial membrane potential (Δψ m) in apoptosis; an update. Apoptosis, 8(2), 115-128.

Majumdar, A., Capetillo-Zarate, E., Cruz, D., Gouras, G. K., & Maxfield, F. R. (2011). Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes. Molecular biology of the cell, 22(10), 1664-1676.

Malm, T., Koistinaho, J., & Kanninen, K. (2011). Utilization of APPswe/PS1dE9 transgenic mice in research of Alzheimer's disease: focus on gene therapy and cell-based therapy applications. International journal of Alzheimer’s disease, 2011.

Mao, X. Q., Yu, F., Wang, N., Wu, Y., Zou, F., Wu, K., Ouyang, J. P. (2009). Hypoglycemic effect of polysaccharide enriched extract of Astragalus membranaceus in diet induced insulin resistant C57BL/6J mice and its potential mechanism. Phytomedicine, 16(5), 416-425. doi:10.1016/j.phymed.2008.12.011

Matheson, P. J., Franklin, G. A., Hurt, R. T., Downard, C. D., Smith, J. W., & Garrison, R. N. (2012). Direct peritoneal resuscitation improves obesity-induced hepatic dysfunction after trauma. J Am Coll Surg, 214(4), 517-528; discussion 528-530. doi:10.1016/j.jamcollsurg.2011.12.016

Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Bateman, R. J. (2010). Decreased clearance of CNS β-amyloid in Alzheimer’s disease. science, 330(6012), 1774-1774.

Mayor, S., & Pagano, R. E. (2007). Pathways of clathrin-independent endocytosis. Nature reviews Molecular cell biology, 8(8), 603.

McGuire, C. M., & Forgac, M. (2018). Glucose starvation increases V-ATPase assembly and activity in mammalian cells through AMP kinase and phosphatidylinositide 3-kinase/Akt signaling. Journal of Biological Chemistry, 293(23), 9113-9123.

Mei, X., Ezan, P., Giaume, C., & Koulakoff, A. (2010). Astroglial connexin immunoreactivity is specifically altered at β-amyloid plaques in β-amyloid precursor protein/presenilin1 mice. Neuroscience, 171(1), 92-105.

Misra, U., Kalita, J., Bhoi, S., & Dubey, D. (2017). Spectrum of hyperosmolar hyperglycaemic state in neurology practice. The Indian journal of medical research, 146(Suppl 2), S1.

Mittal, K., Mani, R. J., & Katare, D. P. (2016). Type 3 diabetes: cross talk between differentially regulated proteins of type 2 diabetes mellitus and Alzheimer’s disease. Scientific reports, 6, 25589.

Mueller-Steiner, S., Zhou, Y., Arai, H., Roberson, E. D., Sun, B., Chen, J., Mucke, L. (2006). Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron, 51(6), 703-714.

Nagele, R. G., Wegiel, J., Venkataraman, V., Imaki, H., Wang, K. C., & Wegiel, J. (2004). Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiology of aging, 25(5), 663-674.

Nhan, H. S., Chiang, K., & Koo, E. H. (2015). The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol, 129(1), 1-19.

Okada, R., Yamauchi, Y., Hongu, T., Funakoshi, Y., Ohbayashi, N., Hasegawa, H., & Kanaho, Y. (2015). Activation of the small G protein Arf6 by dynamin2 through guanine nucleotide exchange factors in endocytosis. Scientific reports, 5, 14919.

Pappolla, M., Sambamurti, K., Vidal, R., Pacheco-Quinto, J., Poeggeler, B., & Matsubara, E. (2014). Evidence for lymphatic Aβ clearance in Alzheimer's transgenic mice. Neurobiology of disease, 71, 215-219.

Park, J., Wetzel, I., Marriott, I., Dréau, D., D’Avanzo, C., Kim, D. Y., ... & Cho, H. (2018). A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nature neuroscience, 21(7), 941-951.

Patterson, C., Feightner, J. W., Garcia, A., Hsiung, G.-Y. R., MacKnight, C., & Sadovnick, A. D. (2008). Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. Canadian Medical Association Journal, 178(5), 548-556.

Peters, K. E., Davis, W. A., Taddei, K., Martins, R. N., Masters, C. L., Davis, T. M., & Bruce, D. G. (2017). Plasma amyloid-β peptides in type 2 diabetes: A matched case-control study. Journal of Alzheimer's Disease, 56(3), 1127-1133.

Phatnani, H., & Maniatis, T. (2015). Astrocytes in neurodegenerative disease. Cold Spring Harb Perspect Biol, 7(6). doi:10.1101/cshperspect.a020628

Pigino, G., Morfini, G., Atagi, Y., Deshpande, A., Yu, C., Jungbauer, L., Brady, S. (2009). Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proceedings of the National Academy of Sciences, 106(14), 5907-5912.

PODDAR, N. K., Mueed, Z., Tandon, P., Maurya, S., Deval, R., & Kamal, M. A. (2018). Tau and mTOR: The hotspots for multifarious diseases in Alzheimer’s development. Frontiers in neuroscience, 12, 1017.

Prasad, H., & Rao, R. (2018). Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH. Proceedings of the National Academy of Sciences, 115(28), E6640-E6649.

Razay, G., Vreugdenhil, A., & Wilcock, G. (2007). The metabolic syndrome and Alzheimer disease. Archives of Neurology, 64(1), 93-96.

Reed-Geaghan, E. G., Savage, J. C., Hise, A. G., & Landreth, G. E. (2009). CD14 and toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. Journal of Neuroscience, 29(38), 11982-11992.

Reiserer, R., Harrison, F., Syverud, D., & McDonald, M. (2007). Impaired spatial learning in the APPSwe+ PSEN1ΔE9 bigenic mouse model of Alzheimer’s disease. Genes, Brain and Behavior, 6(1), 54-65.

Ries, M., & Sastre, M. (2016). Mechanisms of Aβ clearance and degradation by glial cells. Frontiers in aging neuroscience, 8, 160.

Rojas‐Gutierrez, E., Muñoz‐Arenas, G., Treviño, S., Espinosa, B., Chavez, R., Rojas, K., Guevara, J. (2017). Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration. Synapse, 71(10), e21990.

Scuderi, C., Stecca, C., Valenza, M., Ratano, P., Bronzuoli, M., Bartoli, S., Campolongo, P. (2014). Palmitoylethanolamide controls reactive gliosis and exerts neuroprotective functions in a rat model of Alzheimer’s disease. Cell death & disease, 5(9), e1419.

Selkoe, D. J. (1998). The cell biology of β-amyloid precursor protein and presenilin in Alzheimer's disease. Trends in cell biology, 8(11), 447-453.

Sengupta, U., Nilson, A. N., & Kayed, R. (2016). The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine, 6, 42-49.

Shie, F. S., Shiao, Y. J., Yeh, C. W., Lin, C. H., Tzeng, T. T., Hsu, H. C., Liu, H. K. (2015). Obesity and Hepatic Steatosis Are Associated with Elevated Serum Amyloid Beta in Metabolically Stressed APPswe/PS1dE9 Mice. PLoS One, 10(8), e0134531. doi:10.1371/journal.pone.0134531

Shin, E. S., Huang, Q., Gurel, Z., Sorenson, C. M., & Sheibani, N. (2014). High glucose alters retinal astrocytes phenotype through increased production of inflammatory cytokines and oxidative stress. PLoS One, 9(7), e103148.

Sierra, A., Tremblay, M.-È., & Wake, H. (2014). Never-resting microglia: physiological roles in the healthy brain and pathological implications. Frontiers in cellular neuroscience, 8, 240.

Solé-Domènech, S., Cruz, D. L., Capetillo-Zarate, E., & Maxfield, F. R. (2016). The endocytic pathway in microglia during health, aging and Alzheimer’s disease. Ageing research reviews, 32, 89-103.

Soyombo, A. A., Tjon-Kon-Sang, S., Rbaibi, Y., Bashllari, E., Bisceglia, J., Muallem, S., & Kiselyov, K. (2006). TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. Journal of Biological Chemistry, 281(11), 7294-7301.

Sun, L., Zhou, R., Yang, G., & Shi, Y. (2017). Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proceedings of the National Academy of Sciences, 114(4), E476-E485.

Tamaki, C., Ohtsuki, S., & Terasaki, T. (2007). Insulin facilitates the hepatic clearance of plasma amyloid β-peptide (1–40) by intracellular translocation of low-density lipoprotein receptor-related protein 1 (LRP-1) to the plasma membrane in hepatocytes. Molecular pharmacology, 72(4), 850-855.

Tarasoff-Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., Fieremans, E., Zlokovic, B. V. (2015). Clearance systems in the brain—implications for Alzheimer disease. Nature reviews neurology, 11(8), 457.

Tarawneh, R., & Holtzman, D. M. (2012). The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harb Perspect Med, 2(5), a006148. doi:10.1101/cshperspect.a006148

Taylor, R. (2012). Insulin resistance and type 2 diabetes. Diabetes, 61(4), 778-779.
Thal, D. R. (2012). The role of astrocytes in amyloid beta-protein toxicity and clearance. Exp Neurol, 236(1), 1-5. doi:10.1016/j.expneurol.2012.04.021

Torres-Lista, V., & Gimenez-Llort, L. (2013). Impairment of nesting behaviour in 3xTg-AD mice. Behav Brain Res, 247, 153-157. doi:10.1016/j.bbr.2013.03.021
Trudeau, K., Molina, A. J., & Roy, S. (2011). High glucose induces mitochondrial morphology and metabolic changes in retinal pericytes. Investigative ophthalmology & visual science, 52(12), 8657-8664.

Vanhanen, M., Koivisto, K., Moilanen, L., Helkala, E., Hänninen, T., Soininen, H., Kuusisto, J. (2006). Association of metabolic syndrome with Alzheimer disease A population-based study. Neurology, 67(5), 843-847.

Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Loeloff, R. (1999). β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. science, 286(5440), 735-741.

Volianskis, A., Køstner, R., Mølgaard, M., Hass, S., & Jensen, M. S. (2010). Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1ΔE9-deleted transgenic mice model of β-amyloidosis. Neurobiol Aging, 31(7), 1173-1187.

Wang, C., Sun, B., Zhou, Y., Grubb, A., & Gan, L. (2012). Cathepsin B degrades amyloid-β in mice expressing wild-type human amyloid precursor protein. Journal of Biological Chemistry, 287(47), 39834-39841.

Wang, W.-Y., Tan, M.-S., Yu, J.-T., & Tan, L. (2015). Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Annals of translational medicine, 3(10).

Wang, Y. R., Wang, Q. H., Zhang, T., Liu, Y. H., Yao, X. Q., Zeng, F., Wang, Y. J. (2017). Associations Between Hepatic Functions and Plasma Amyloid-Beta Levels-Implications for the Capacity of Liver in Peripheral Amyloid-Beta Clearance. Mol Neurobiol, 54(3), 2338-2344. doi:10.1007/s12035-016-9826-1

Wanrooy, B. J., Kumar, K. P., Wen, S. W., Qin, C. X., Ritchie, R. H., & Wong, C. H. (2018). Distinct contributions of hyperglycemia and high-fat feeding in metabolic syndrome-induced neuroinflammation. Journal of neuroinflammation, 15(1), 293.
Wilkinson, K., & El Khoury, J. (2012). Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer's disease. International journal of Alzheimer’s disease, 2012.

Wu, P., Shi, X., Luo, M., Li, K., Zhang, M., Ma, J., Liu, X. (2019). Taurine inhibits neuron apoptosis in hippocampus of diabetic rats and high glucose exposed HT-22 cells via the NGF-Akt/Bad pathway. Amino Acids, 1-16.

Wu, Y., WU, K., & WANG, Y. (2005). Hypoglycemic effect of Astragalus polysaccharide and its effect on PTP1B1. Acta Pharmacologica Sinica, 26(3), 345-352.

Xiao, Q., Yan, P., Ma, X., Liu, H., Perez, R., Zhu, A., . . . Cirrito, J. R. (2014). Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis. Journal of Neuroscience, 34(29), 9607-9620.

Xiong, H., Callaghan, D., Wodzinska, J., Xu, J., Premyslova, M., Liu, Q.-Y., Zhang, W. (2011). Biochemical and behavioral characterization of the double transgenic mouse model (APPswe/PS1dE9) of Alzheimer’s disease. Neuroscience bulletin, 27(4), 221.

Xu, L., He, D., & Bai, Y. (2016). Microglia-mediated inflammation and neurodegenerative disease. Mol Neurobiol, 53(10), 6709-6715.

Yang, Y., Wu, Y., Zhang, S., & Song, W. (2013). High glucose promotes Aβ production by inhibiting APP degradation. PLoS One, 8(7), e69824.

Yeh, C. W., Liu, H. K., Lin, L. C., Liou, K. T., Huang, Y. C., Lin, C. H., Shiao, Y. J. (2017). Xuefu Zhuyu decoction ameliorates obesity, hepatic steatosis, neuroinflammation, amyloid deposition and cognition impairment in metabolically stressed APPswe/PS1dE9 mice. J Ethnopharmacol, 209, 50-61. doi:10.1016/j.jep.2017.07.036

Yeh, C. W., Yeh, S. H., Shie, F. S., Lai, W. S., Liu, H. K., Tzeng, T. T., Shiao, Y. J. (2015). Impaired cognition and cerebral glucose regulation are associated with astrocyte activation in the parenchyma of metabolically stressed APPswe/PS1dE9 mice. Neurobiol Aging, 36(11), 2984-2994. doi:10.1016/j.neurobiolaging.2015.07.022

Yin, Z., Raj, D., Saiepour, N., Van Dam, D., Brouwer, N., Holtman, I. R., Boddeke, E. (2017). Immune hyperreactivity of Abeta plaque-associated microglia in Alzheimer's disease. Neurobiol Aging, 55, 115-122. doi:10.1016/j.neurobiolaging.2017.03.021

Zhang, J. (2015). Teaching the basics of autophagy and mitophagy to redox biologists—mechanisms and experimental approaches. Redox biology, 4, 242-259.

Zhang, Y. W., Wu, C. Y., & Cheng, J. T. (2007). Merit of Astragalus polysaccharide in the improvement of early diabetic nephropathy with an effect on mRNA expressions of NF-kappaB and IkappaB in renal cortex of streptozotoxin-induced diabetic rats. J Ethnopharmacol, 114(3), 387-392. doi:10.1016/j.jep.2007.08.024

Zhao, C., Deng, W., & Gage, F. H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell, 132(4), 645-660.

Zhao, L. H., Ma, Z. X., Zhu, J., Yu, X. H., & Weng, D. P. (2011). Characterization of polysaccharide from Astragalus radix as the macrophage stimulator. Cell Immunol, 271(2), 329-334. doi:10.1016/j.cellimm.2011.07.011

Zhao, M., Zhang, Z. F., Ding, Y., Wang, J. B., & Li, Y. (2012). Astragalus polysaccharide improves palmitate-induced insulin resistance by inhibiting PTP1B and NF-kappaB in C2C12 myotubes. Molecules, 17(6), 7083-7092. doi:10.3390/molecules17067083

Zorova, L. D., Popkov, V. A., Plotnikov, E. Y., Silachev, D. N., Pevzner, I. B., Jankauskas, S. S., Juhaszova, M. (2018). Mitochondrial membrane potential. Analytical biochemistry, 552, 50-59.