The Effect of Curcumin on Aβ, Akt, and GSK3β in Brain and Retina of APP/PS1 Mice and Blood of Alzheimer’s Patients With Early Stage Disease

doi:10.21203/rs.3.rs-880130/v1

Download PDF

Research

The Effect of Curcumin on Aβ, Akt, and GSK3β in Brain and Retina of APP/PS1 Mice and Blood of Alzheimer’s Patients With Early Stage Disease

https://doi.org/10.21203/rs.3.rs-880130/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

Curcumin has multifunctional pharmacological properties, including anti-oxidant, anti-inﬂammatory, and anti-diabetic properties. We investigated whether curcumin can improve pathological changes associated with Alzheimer's disease, including amyloid β (Aβ), protein kinase B (PKB, also termed Akt), and glycogen synthase kinase 3β (GSK3β) levels and expression.

Methods

Alzheimer’s transgenic APP_SWE/PS1_ΔE9 mice and wild type mice were treated with curcumin by intragastric administration for 2 weeks at 2 and 5 months of age. Aβ plaques and contents in the brain and retina were measured by immunohistochemistry and enzyme-linked immune sorbent assay, respectively, while the expression of Akt and GSK3β was tested by RNA isolation and quantitative real-time poly merase chain reaction. Bloods of patients with AD and age-matched health controls were used to determine the contents of Aβ, Akt and GSK3β.

Results

Curcumin treatment decreased Aβ accumulation in the early stages of AD at 5 months (p < 0.001). It also improved AD-associated pathological changes, including upregulation of Akt (p < 0.01) and downregulation of GSK3β (p < 0.01). In addition to AD-associated changes, the proinflammatory cytokine IL-1β was significantly decreased by curcumin treatment (p < 0.05).

Conclusions

Curcumin can suppress Aβ accumulation during the early stages of AD, upregulate the expression of Akt, downregulate the expression of GSK3β, and inhibit the proinflammatory cytokine IL-1β. Curcumin can be used to improve pathological features of AD in the early stages of disease

Internal Medicine

Curcumin

Aβ

Akt

GSK3β

brain

retina

early stage of AD

In Alzheimer’s disease (AD), accumulation of amyloid β (Aβ) is one of the key processes in disease progression and a key mediator of synaptic dysfunction and cognitive impairment [1]. Aβ regulates protein kinase B (PKB, also termed Akt) and glycogen synthase kinase 3β (GSK3β) signaling, which interact with each other in the AD brain [2,3]. Additionally, Aβ production may also be regulated by GSK3 [4].

Previous studies have suggested that the AKT/GSK-3b pathway plays a key role in the maintenance of neuronal survival and neuronal networks in AD [5,6]. Pharmacological activation of Akt rescued memory impairment in Aβ-injected AD model mice [7]. Disturbance of the AKT/GSK-3b signaling pathway is a key mechanism underlying the pathophysiology of both neurodegenerative diseases and diabetes mellitus [8,9].

Curcumin is the main active component of the traditional Chinese medicine turmeric, which has anti-inflammatory, anti-oxidant, and anti-tumor effects [10]. Previous curcumin human tolerance tests and clinical research on the effect of curcumin treatment of AD have shown that the probability of digestive tract intolerance is very small [11].

Animal experiments have shown that after one week of curcumin treatment, the number of Aβ plaques in the brains of APP_SWE/PS1_ΔE9 (APP/PS1) transgenic mice was significantly reduced [12,13]. The ability of curcumin to effectively clear Aβ is likely due to ability to breakdown products within the body.

In recent years, the neuroprotective effect of curcumin has become a research focus. It has been found that curcumin can improve cognition and inhibit inflammation by regulating related cell pathways, including regulating BDNF and Akt/GSK3β signaling pathways to improve the cognitive decline of rats caused by intracerebroventricular injection of Aβ₄₂ [14].

Studies into curcumin treatment of spinal injuries shows that curcumin can regulate the TLR4/NF-κB signaling pathway by downregulating the levels of TLR4, NF-κB, and inflammatory cytokines, thereby protecting against spinal injury [15]. In Aβ-stimulated microglia, curcumin can block NF-κB, JNK, and p38 MAPK signaling pathways, which produce anti-inflammatory effects, and protect hippocampal HT-22 cells from the neurotoxic effects caused by microglial activation [16]. Curcumin can also regulate the PTEN/Akt/GSK3β pathway and inhibit tau hyperphosphorylation caused by Aβ in SH-SY5Y cells [17]. Curcumin can inhibit inflammatory gene expression and pro-inflammatory pathways by inhibiting NF-κB activity [18].

To date, many studies have reported that curcumin improves cognitive function by inhibiting Aβ accumulation in APP/PS1 mice [19]. However, it remains unclear whether curcumin can prevent neuronal injury via the AKT/GSK-3b signaling pathway. In the present study, we investigated the effect of curcumin on Aβ in vivo and the protein expression of AKT and GSK-3b by immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR) analysis.

Animals

APP/PS1 transgenic mice and age-matched wild-type (WT) mice were provided by the Model Animal Research Center of Nanjing University (Nanjing, China). To exclude the effect of sex on the results, only male mice were used. Animals were housed in cages in a room maintained at 22±2°C and 60±5% relative humidity under a 12-h light–dark cycle (lights on at 6:00 am). Water and food were available ad libitum. Animal experiments were conducted outside the housing area in a separate room.

Patients

Nineteen AD patients and twenty age-matched healthy controls (HCs) were recruited for the study. AD patients with no retinal diseases aged between 60 and 88 years were diagnosed by two research psychiatrists according to the standards of the National Institution of Neurologic and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association, NINCDSADRDA and Diagnostic and Statistical Manual of Mental Disorders, DSM.

Drug preparation and administration

Curcumin (pure curcumin ≥ 80%, Hushi, Shanghai, China) was dissolved in phosphate buffered saline (PBS, 0.1 M Na₂HPO₄, 0.1 M KH₂PO₄, 0.1 M KCl, and 0.1 M NaCl, pH 7.4). Animals were divided at the age of 2 and 5 months into four experimental groups (n = 15 mice/group): (1) APP/PS1 mice treated with curcumin (0.1 mg/g) dissolved in PBS; (2) APP/PS1 mice treated with a similar volume of only PBS; (3) WT mice treated with curcumin (0.1 mg/g) dissolved in PBS; and (4) WT mice treated with a similar volume of only PBS. All treatments were administered intragastrically for two weeks.

Aβ immunohistochemistry

Briefly, after anesthetization, mice were perfused with saline until the limbs and the liver turned white, and then perfused with 4% paraformaldehyde until the tail became stiff. The brain tissue was dissected and incubated with 4% paraformaldehyde for 1 d. After washing with PBS, the tissue was placed in a centrifuge tube containing 30% sucrose solution until the brain tissue sunk to the bottom. A cryostat was used to cut the brain tissue into 25 μm thick sections. The sections were incubated in 1% bovine serum albumin (BSA) for 1 h and then incubated with β-amyloid antibody (1: 500, Cell Signaling Technology) at 4°C overnight. The sections were washed three times with PBS, rinsed, and incubated with the secondary antibody at 37°C for 1 h. After staining with 4,6-diamidino-2-phenylindole (DAPI) for 1 min, the sections were washed three times with PBS and imaged using a confocal fluorescence microscope

Enzyme-linked immune sorbent assay (ELISA)

The Aβ and IL-1β levels in the mouse brain, retina, and human blood were measured by ELISA (MyBioSource, CA, USA). Absorbance at 450 nm (at a reference wavelength of 690 nm) was measured using an absorbance reader (Sunrise™, Tecan, Geneva, Switzerland). The absorbance value was transformed into a concentration value by reading the absorbance of pure samples on a standard curve.

RNA isolation and quantitative real-time polymerase chain reaction (RT-qPCR)

Akt and GSK3β expression was determined by RT-qPCR. Total cellular RNA was isolated using RNAiso Plus reagent (Takara Bio Inc., Otsu, Japan) according to the manufacturer’s instructions.

Determination of serum Aβ, Akt, GSK3β, and IL-1β levels

Serum Aβ, Akt, GSK3β, and IL-1β levels were estimated using an ELISA assay kit (MyBioSource, CA, USA). All procedures were performed according to the manufacturer’s instructions.

Mini-mental state examination (MMSE)

MMSE, which involves scores ranging from 0 to 30, was adopted to evaluate the cognitive levels of all subjects. Lower MMSE scores indicate poorer cognitive performance.

Statistical analyses

Data are presented as the mean ± standard error. Prism v7.0 (GraphPad, San Diego, CA, USA) was used for statistical analyses. Differences among multiple mean ± SE values were assessed by one-way and two-way ANOVA, followed by Bonferroni’s post hoc test. Differences between two mean ± SE values were assessed using unpaired t-tests. Statistical significance was set at P < 0.05.

Table1 Demographic and clinical characteristics of all subjects

Variables	AD patients (n=9)	Health controls (n=10)	p value
Age (year)	72.56±10.27	73.91±7.82	0.368
Sex (male)	5	6	-
BMI	21.89±2.78	21.64±2067	0.815
Education years	10.33±3.08	10.46±2.58	0.505
MMSE	10.89±7.52	27.82±1.78	0.001

Curcumin reduced Aβ protein levels in AD mice

Aβ plaques were stained by immunohistochemistry (Figure 1), and the levels of total Aβ in the cortex analyzed using a specific sandwich ELISA are shown in Figure 2. As shown in Figure 1, curcumin treatment reduced the amount of positive staining for Aβ in the cortex of APP/PS1 mice at 5 months, which represents the early stage of AD.

There was no obvious effect of curcumin on Aβ levels in the 2 month old mice (Figure 2). However, in the 5 months old mice, curcumin treatment decreased the Aβ levels in both the cortex and retina of the APP/PS1 group (p < 0.05).

Curcumin modulate the Akt and GSK3β expressions in AD mice

Compared to WT, the gene expression of Akt was significantly decreased (p < 0.01), whereas the gene expression of GSK3β was significantly elevated (p < 0.05) in the brain and retina of APP/PS1 mice (Figure 3). After administration of curcumin, the APP/PS1 mice showed a significant decline in the expression of GSK3β at 2 months (p < 0.01) and elevation of Akt gene expression at both 2 and 5 months (p < 0.01).

Effect of curcumin on inflammatory mediators in AD mice

Levels of IL-1β measured from the soluble fraction of the brain and retina of mice at 2 and 5 months are shown in Figure 4. Compared to the WT group, APP/PS1 mice showed significantly elevated levels of IL-1β (p < 0.001). Moreover, compared to the APP/PS1 group, the curcumin treatment group exhibited a significant decrease in IL-1β levels (p < 0.001).

Difference in Aβ, Akt, GSK3β, and proinflammatory cytokines between AD patients and health subjects

The demographics and clinical characteristics of the study subjects are detailed in Table 1. Mean age of AD was 72.56 ± 10.27 years, 55.56% were male, BMI was 21.89 ± 2.78, education was 10.33 ± 3.08 years, MMSE score was 10.89 ± 7.52 and mean disease course was 7.22 ± 2.82 years. There were significant differences in the mean MMSE scores between the AD and HC groups (p < 0.01). There were no differences in age, BMI, or education level between the groups (p > 0.05).

Figure 5 shows the levels of Aβ, Akt, GSK3β, and IL-1β in the serum of AD patients and healthy controls. There was a significant difference between groups in Akt levels (p < 0.05), however no difference was found in Aβ, GSK3β, and IL-1β.

Neurodegenerative diseases can affect both the brain and the retina. Although the neuroprotective effect of curcumin has already been studied, it was not yet known whether curcumin can directly influence Aβ accumulation, proinflammatory cytokines, and related proteases. The current study investigated the effect of curcumin on Aβ, Akt, and GSK3β in the brain and retina of APP/PS1 mice.

The ageing process can cause a large amount of Aβ accumulation may disrupt the immune response and produce local inflammation[8]. Additionally, Aβ clearance can be decreased due to insulin resistance [20]. Using APPswe/PS1dE9 transgenic mice, we found that Aβ plaques were observed largely at 5 months compared to 2 months. We noticed that WT mice also had high amount of Aβ in the cortex with mouse age. Aβ content increased, but Aβ plaques have not yet formed. Similarly, the pro-inflammatory cytokine IL-1β also increased with mouse age. Previous studies have suggested that sustained inflammation results in chronic Aβ deposition, which eventually leads to AD [21]. In patients with insulin resistance, there may be an inflammatory microenvironment.

GSK3β plays a key role in insulin resistance. One of the features of insulin resistance is the impaired insulin/P13K/Akt pathway, which leads to an increase in GSK3β [22]. In APP/PS1 mice, the gene expression of GSK3β was significantly increased (p < 0.05) in the brain and retina, whereas gene expression of Akt was significantly decreased (p < 0.01). Besides its role in AD, inhibition of GSK3β activity can also prevent pathological changes in diabetes mellitus [23]. There is evidence to suggest that AD is the third type of diabetes mellitus. GSK3β was highly expressed in the human data from this study, which is in line with previous works [24,25]. The therapeutic potential of GSK3β inhibition has been investigated in several preclinical AD studies, which show that levels of tau phosphorylation and Aβ deposition can be suppressed by GSK3β inhibitors [26,27]. Compared with normal individuals, Akt expression was significantly decreased in AD patients. Akt activator influences AD-like memory impairment and LTP impairment [7].

Curcumin has multifunctional pharmacological effects, including anti-oxidant, anti-inflammatory, and anti-diabetic properties [28-31]. The current study found an inhibitory effect of curcumin on brain and retina Aβ levels and investigated the neuroprotective mechanism and the improvement of brain diseases that may result from this effect. Curcumin can also be used as an imaging agent for Aβ plaques [13]. Therefore, in addition to the neuroprotective effects of curcumin, further research on the diagnosis and treatment of curcumin with eye brain-related diseases is required in the future [32,33].

The limitation of this study was that only changes in Aβ, Akt, and GSK3β were investigated, and not the pathway changes of Akt/GSK3β. It is important to investigate a full range of pathological pathways in the AD brain, to enable to development of more therapeutic targets for AD treatment.

In conclusion, this study found that curcumin appears to suppress Aβ accumulation during the early stage of AD, upregulate the expression of Akt, downregulate the expression of GSK3β, and inhibit the proinflammatory cytokine IL-1β. This suggests that curcumin treatment may be useful to improve pathological features of AD in the early stages of disease.

Alzheimer’s disease (AD)

amyloid β (Aβ)

protein kinase B (PKB, also termed Akt),

glycogen synthase kinase 3β (GSK3β)

APPSWE/PS1ΔE9 (APP/PS1)

real-time quantitative polymerase chain reaction (RT-qPCR)

wild-type (WT)

healthy controls (HCs)

phosphate buffered saline (PBS)

4,6-diamidino-2-phenylindole (DAPI)

Enzyme-linked immune sorbent assay (ELISA)

Mini-mental state examination (MMSE)

Acknowledgement

We thank Prof. Wei Cui of Ningbo University for providing the useful discussion.

Statement of Ethics

All animal experiments were performed according to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80-23, revised 1996) and were approved by the Institutional Animal Care and Use Committee of the Medical School of Ningbo University (Ningbo, China).

This study was approved by the local Ethics Committee of Ningbo Kangning Hospital (NBKNYY-2018-LC-21) and registered as a clinical trial in the China Clinical Trial Registry (CHICTR: ChiCTR2000035243). All procedures of the study were in accordance with the Helsinki Declaration (2014) ethical standards and regulations for human research.

Conflict of Interest

No competing interests

Funding

This study was supported by the Zhejiang Provincial Natural and Science Fund (LQ19F010003), Natural Science Foundation of Ningbo (2019A610355) and Zhejiang Medical and Health Science and Technology Project (2021KY1066).

Author Contributions

XM, XL and MY performed animal experiments, data collection and wrote the manuscript. XM, CQ, and JH performed data analysis. CZ, and ZC proofread the manuscript. All authors read and approved the final manuscript.

Data Availability Statement.

All data are included in the manuscript. However, the raw data used and/or analyzed in the present study are available from the corresponding author on reasonable request.

Consent to publish

Not applicable

1 Hardy J, Selkoe DJ: The amyloid hypothesis of alzheimer's disease: Progress and problems on the road to therapeutics. Science (New York, NY) 2002;297:353-356.

2 Huang W, Cheng P, Yu K, Han Y, Song M, Li Y: Hyperforin attenuates aluminum-induced aβ production and tau phosphorylation via regulating akt/gsk-3β signaling pathway in pc12 cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2017;96:1-6.

3 Lauretti E, Dincer O, Praticò D: Glycogen synthase kinase-3 signaling in alzheimer's disease. Biochimica et biophysica acta Molecular cell research 2020;1867:118664.

4 Chu J, Lauretti E, Praticò D: Caspase-3-dependent cleavage of akt modulates tau phosphorylation via gsk3β kinase: Implications for alzheimer's disease. Molecular psychiatry 2017;22:1002-1008.

5 Zheng R, Zhang ZH, Chen C, Chen Y, Jia SZ, Liu Q, Ni JZ, Song GL: Selenomethionine promoted hippocampal neurogenesis via the pi3k-akt-gsk3β-wnt pathway in a mouse model of alzheimer's disease. Biochemical and biophysical research communications 2017;485:6-15.

6 Yao Y, Wang Y, Kong L, Chen Y, Yang J: Osthole decreases tau protein phosphorylation via pi3k/akt/gsk-3β signaling pathway in alzheimer's disease. Life sciences 2019;217:16-24.

7 Yi JH, Baek SJ, Heo S, Park HJ, Kwon H, Lee S, Jung J, Park SJ, Kim BC, Lee YC, Ryu JH, Kim DH: Direct pharmacological akt activation rescues alzheimer's disease like memory impairments and aberrant synaptic plasticity. Neuropharmacology 2018;128:282-292.

8 Zhang Y, Huang NQ, Yan F, Jin H, Zhou SY, Shi JS, Jin F: Diabetes mellitus and alzheimer's disease: Gsk-3β as a potential link. Behavioural brain research 2018;339:57-65.

9 Gao C, Hölscher C, Liu Y, Li L: Gsk3: A key target for the development of novel treatments for type 2 diabetes mellitus and alzheimer disease. Reviews in the neurosciences 2011;23:1-11.

10 Kotha RR, Luthria DL: Curcumin: Biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules (Basel, Switzerland) 2019;24

11 Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG, Porter V, Vanek Z, Marshall GA, Hellemann G, Sugar C, Masterman DL, Montine TJ, Cummings JL, Cole GM: Oral curcumin for alzheimer's disease: Tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimer's research & therapy 2012;4:43.

12 Yanagisawa D, Kato T, Taguchi H, Shirai N, Hirao K, Sogabe T, Tomiyama T, Gamo K, Hirahara Y, Kitada M, Tooyama I: Keto form of curcumin derivatives strongly binds to aβ oligomers but not fibrils. Biomaterials 2021;270:120686.

13 Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ: Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an alzheimer mouse model. Journal of neurochemistry 2007;102:1095-1104.

14 Hoppe JB, Coradini K, Frozza RL, Oliveira CM, Meneghetti AB, Bernardi A, Pires ES, Beck RC, Salbego CG: Free and nanoencapsulated curcumin suppress β-amyloid-induced cognitive impairments in rats: Involvement of bdnf and akt/gsk-3β signaling pathway. Neurobiology of learning and memory 2013;106:134-144.

15 Ni H, Jin W, Zhu T, Wang J, Yuan B, Jiang J, Liang W, Ma Z: Curcumin modulates tlr4/nf-κb inflammatory signaling pathway following traumatic spinal cord injury in rats. The journal of spinal cord medicine 2015;38:199-206.

16 Park SY, Jin ML, Kim YH, Kim Y, Lee SJ: Anti-inflammatory effects of aromatic-turmerone through blocking of nf-κb, jnk, and p38 mapk signaling pathways in amyloid β-stimulated microglia. International immunopharmacology 2012;14:13-20.

17 Huang HC, Tang D, Xu K, Jiang ZF: Curcumin attenuates amyloid-β-induced tau hyperphosphorylation in human neuroblastoma sh-sy5y cells involving pten/akt/gsk-3β signaling pathway. Journal of receptor and signal transduction research 2014;34:26-37.

18 Jain SK, Rains J, Croad J, Larson B, Jones K: Curcumin supplementation lowers tnf-alpha, il-6, il-8, and mcp-1 secretion in high glucose-treated cultured monocytes and blood levels of tnf-alpha, il-6, mcp-1, glucose, and glycosylated hemoglobin in diabetic rats. Antioxidants & redox signaling 2009;11:241-249.

19 Mei X, Zhu L, Zhou Q, Li X, Chen Z: Interplay of curcumin and its liver metabolism on the level of aβ in the brain of app(swe)/ps1(de9) mice before ad onset. Pharmacological reports : PR 2020;72:1604-1613.

20 Wakabayashi T, Yamaguchi K, Matsui K, Sano T, Kubota T, Hashimoto T, Mano A, Yamada K, Matsuo Y, Kubota N, Kadowaki T, Iwatsubo T: Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of alzheimer's disease. 2019;14:15.

21 Huang NQ, Jin H, Zhou SY, Shi JS, Jin F: Tlr4 is a link between diabetes and alzheimer's disease. Behavioural brain research 2017;316:234-244.

22 Liolitsa D, Powell J, Lovestone S: Genetic variability in the insulin signalling pathway may contribute to the risk of late onset alzheimer's disease. Journal of neurology, neurosurgery, and psychiatry 2002;73:261-266.

23 Wang Y, Feng W, Xue W, Tan Y, Hein DW, Li XK, Cai L: Inactivation of gsk-3beta by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes 2009;58:1391-1402.

24 Gupta SC, Kismali G, Aggarwal BB: Curcumin, a component of turmeric: From farm to pharmacy. BioFactors (Oxford, England) 2013;39:2-13.

25 Aggarwal BB: Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annual review of nutrition 2010;30:173-199.

26 Ghorbani Z, Hekmatdoost A, Mirmiran P: Anti-hyperglycemic and insulin sensitizer effects of turmeric and its principle constituent curcumin. International journal of endocrinology and metabolism 2014;12:e18081.

27 Zhu HT, Bian C, Yuan JC, Chu WH, Xiang X, Chen F, Wang CS, Feng H, Lin JK: Curcumin attenuates acute inflammatory injury by inhibiting the tlr4/myd88/nf-κb signaling pathway in experimental traumatic brain injury. Journal of neuroinflammation 2014;11:59.

28 Zhu W, Wu Y, Meng YF, Wang JY, Xu M, Tao JJ, Lu J: Effect of curcumin on aging retinal pigment epithelial cells. Drug design, development and therapy 2015;9:5337-5344.

29 Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller CA, Ko MK, Black KL, Schwartz M, Farkas DL: Identification of amyloid plaques in retinas from alzheimer's patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. NeuroImage 2011;54 Suppl 1:S204-217.

30 Leroy K, Brion JP: Developmental expression and localization of glycogen synthase kinase-3beta in rat brain. Journal of chemical neuroanatomy 1999;16:279-293.

31 Leroy K, Yilmaz Z, Brion JP: Increased level of active gsk-3beta in alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathology and applied neurobiology 2007;33:43-55.

32 Serenó L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I, Agulló JM, Pérez M, Avila J, Guardia-Laguarta C, Clarimón J, Lleó A, Gómez-Isla T: A novel gsk-3beta inhibitor reduces alzheimer's pathology and rescues neuronal loss in vivo. Neurobiology of disease 2009;35:359-367.

33 Wang H, Huang S, Yan K, Fang X, Abussaud A, Martinez A, Sun HS, Feng ZP: Tideglusib, a chemical inhibitor of gsk3β, attenuates hypoxic-ischemic brain injury in neonatal mice. Biochimica et biophysica acta 2016;1860:2076-2085.

Download PDF

Version 1

posted

You are reading this latest preprint version

The Effect of Curcumin on Aβ, Akt, and GSK3β in Brain and Retina of APP/PS1 Mice and Blood of Alzheimer’s Patients With Early Stage Disease

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Status:

Version 1