Escitalopram Alleviates Alzheimer’s Disease-Type Tau Pathologies in the Aged P301L Tau Transgenic Mice

2020 ◽  
Vol 77 (2) ◽  
pp. 807-819
Author(s):  
Yan-Juan Wang ◽  
Wei-Gang Gong ◽  
Qing-Guo Ren ◽  
Zhi-Jun Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Phosphorylation ◽  
Tau Hyperphosphorylation ◽  
Protective Effects ◽  
Protein Levels ◽  
Phosphorylated Akt ◽  
Biochemical Analyses ◽  
Gsk 3Β

Background: The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer’s disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro. Objective: In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. Methods: Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. Results: Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3β and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. Conclusion: The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3β signaling pathway.

scholarly journals A TauP301L mouse model of dementia; development of pathology, synaptic transmission, microglial response and cognition throughout life

2018 ◽  
Author(s):  
Zelah Joel ◽  
Pablo Izquierdo ◽  
Wenfei Liu ◽  
Chloe Hall ◽  
Martha Roberts ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Transmission ◽  
Neurofibrillary Tangles ◽  
Late Stage ◽  
Tau Hyperphosphorylation ◽  
Protein Levels ◽  
Field Recordings ◽  
Plaque Load

AbstractBackgroundLate stage Alzheimer’s disease and other dementias are associated with neurofibrillary tangles and neurodegeneration. Here we describe a mouse (TauD35) carrying human Tau with the P301L mutation that results in Tau hyperphosphorylation and tangles. Previously we have compared gene expression in TauD35 mice to mice which develop plaques but no tangles. A similar comparison of other pathological features throughout disease progression is made here between amyloidβ and Tau mice described in Parts I and II of this study.MethodsIn vitro CA1 patch clamp and field recordings were used to investigate synaptic transmission and plasticity. Plaque load and microglia were investigated with immunohistochemistry. Cognition, locomotor activity and anxiety-related behaviours were assessed with a forced-alternation T-maze, open field and light/dark box.ResultsTransgene copy number in TauD35 mice fell into two groups (HighTAU and LowTAU), allowing assessment of dose-dependent effects of overexpression and resulting in tangle load increasing 100-fold for a 2-fold change in protein levels. Tangles were first detected at 8 (HighTAU) or 13 months (LowTAU) but the effects on synaptic transmission and plasticity and behaviour were subtle. However, severe neurodegeneration occurred in HighTAU mice at around 17 months, preceded by considerable proliferation and activation of microglia at 13 months of age; both increasing further at 17 months. LowTAU mice at 24 months of age showed a comparable tangle load and microglial proliferation to that occurring at 13 months in HighTAU mice. However, LowTAU mice showed no neurodegeneration at this stage and considerable microglial activation, stressing the dependence of these effects on overexpression and/or age.ConclusionsComparison of the effects of amyloidβ and plaques without tangles in a model of preclinical Alzheimer’s disease to the effects of tangles without amyloidβ plaques in the late stage model described here may clarify the progressive stages of Alzheimer’s disease. While Tau hyperphosphorylation and neurofibrillary tangles are eventually sufficient to cause severe neurodegeneration, initial effects on synaptic transmission and the immune response are subtle. In contrast while even with a heavy plaque load little if any neurodegeneration occurs, considerable effects on synaptic transmission and the immune system result, even before plaques are detectable.

scholarly journals Administration of Momordica charantia Enhances the Neuroprotection and Reduces the Side Effects of LiCl in the Treatment of Alzheimer’s Disease

Nutrients ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 1888 ◽  
Author(s):  
Hei-Jen Huang ◽  
Shu-Ling Chen ◽  
Yen-Ting Chang ◽  
Jong-Ho Chyuan ◽  
Hsiu Hsieh-Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Side Effects ◽  
Neuroprotective Effect ◽  
Combined Treatment ◽  
Momordica Charantia ◽  
Natural Food ◽  
Tau Hyperphosphorylation ◽  
Protective Effects

Recently, the use of natural food supplements to reduce the side effects of chemical compounds used for the treatment of various diseases has become popular. Lithium chloride (LiCl) has some protective effects in neurological diseases, including Alzheimer’s disease (AD). However, its toxic effects on various systems and some relevant interactions with other drugs limit its broader use in clinical practice. In this study, we investigated the in vitro and in vivo pharmacological functions of LiCl combined with Momordica charantia (MC) in the treatment of AD. The in vitro results show that the order of the neuroprotective effect is MC5, MC3, MC2, and MC5523 under hyperglycemia or tau hyperphosphorylation. Therefore, MC5523 (80 mg/kg; oral gavage) and/or LiCl (141.3 mg/kg; intraperitoneal injection) were applied to ovariectomized (OVX) 3×Tg-AD female and C57BL/6J (B6) male mice that received intracerebroventricular injections of streptozotocin (icv-STZ, 3 mg/kg) for 28 days. We found that the combined treatment not only increased the survival rate by reducing hepatotoxicity but also increased neuroprotection associated with anti-gliosis in the icv-STZ OVX 3×Tg-AD mice. Furthermore, the cotreatment with MC5523 and LiCl prevented memory deficits associated with reduced neuronal loss, gliosis, oligomeric Aβ level, and tau hyperphosphorylation and increased the expression levels of synaptic-related protein and pS9-GSK3β (inactive form) in the icv-STZ B6 mice. Therefore, MC5523 combined with LiCl could be a potential strategy for the treatment of AD.

Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

2020 ◽  
Vol 20 (12) ◽  
pp. 1059-1073 ◽  
Author(s):  
Ahmad Abu Turab Naqvi ◽  
Gulam Mustafa Hasan ◽  
Md. Imtaiyaz Hassan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Glycogen Synthase ◽  
Paired Helical Filaments ◽  
Tau Hyperphosphorylation ◽  
Microtubule Stabilization ◽  
Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

Genipin Attenuates Tau Phosphorylation and Aβ Levels in Cellular Models of Alzheimer's Disease

2021 ◽  
Author(s):  
Meiting Li ◽  
Nan Cai ◽  
Liang Gu ◽  
Lijun Yao ◽  
Decheng Bi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Tau Phosphorylation ◽  
Brain Disorder ◽  
Cellular Models ◽  
Aβ Generation ◽  
Aβ Production

Abstract Alzheimer’s disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules are considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.

scholarly journals Effect of Herbal Medicinal Compounds on Alzheimer’s Disease Pathology in APP/PS1 Transgenic Mouse Model

2020 ◽  
Vol 15 (8) ◽  
pp. 1934578X2094898
Author(s):  
Xuexia Li ◽  
Zhijun He ◽  
Chao Wang ◽  
Yanjun Liu ◽  
Zhifu Shan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herbal Medicines ◽  
Protective Effects ◽  
Multiple Targets ◽  
Aβ Oligomers ◽  
Protein Levels ◽  
Medicinal Compounds ◽  
Single Target ◽  
Herbal Medicinal

The pathogenesis of Alzheimer’s disease (AD) is complex as various mechanisms interact with each other and, therefore, intervention from a single target is often ineffective. Many studies have shown that herbal medicines, such as curcumin, fisetin, icariin, and ginsenosides, have significant intervention effects on AD with different treatment mechanisms. Therefore, we have designed this study to know whether the combination of these herbal medicines can have an intervention effect on AD through multiple targets. Amyloid precursor protein/presenilin 1(APP/PS1) double transgenic AD mice were used to study the protective effects of a combination of curcumin, piperine, icariin, and ginsenosides, as well as a combination of fisetin, piperine, icariin, and ginsenosides, which were separately mixed into the feed. These herbal medicinal compounds (HMCs) lowered the serum lipid levels, reduced the Aβ oligomers, decreased the pS404-tau protein, as well as neurofibrillary tangles, and restored the reduction of synaptic protein levels and neuronal death of AD mice without causing toxicity to liver and kidneys. In this study, we found that HMCs have significant intervention against AD through multiple targets, providing a novel therapeutic idea for the prevention of AD.

scholarly journals RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer’s disease

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Leticia Pérez-Sisqués ◽  
Anna Sancho-Balsells ◽  
Júlia Solana-Balaguer ◽  
Genís Campoy-Campos ◽  
Marcel Vives-Isern ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Mrna Levels ◽  
Spine Density ◽  
Memory Impairments ◽  
Protein Levels ◽  
Synaptic Markers ◽  
5Xfad Mice

AbstractRTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death. Its downregulation in Parkinson’s and Huntington’s disease models ameliorates the pathological phenotypes. In the context of Alzheimer’s disease (AD), the coding gene for RTP801, DDIT4, is responsive to Aβ and modulates its cytotoxicity in vitro. Also, RTP801 mRNA levels are increased in AD patients’ lymphocytes. However, the involvement of RTP801 in the pathophysiology of AD has not been yet tested. Here, we demonstrate that RTP801 levels are increased in postmortem hippocampal samples from AD patients. Interestingly, RTP801 protein levels correlated with both Braak and Thal stages of the disease and with GFAP expression. RTP801 levels are also upregulated in hippocampal synaptosomal fractions obtained from murine 5xFAD and rTg4510 mice models of the disease. A local RTP801 knockdown in the 5xFAD hippocampal neurons with shRNA-containing AAV particles ameliorates cognitive deficits in 7-month-old animals. Upon RTP801 silencing in the 5xFAD mice, no major changes were detected in hippocampal synaptic markers or spine density. Importantly, we found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD.

Plant Compound Curcumin Mediates Calcineurin Activity to Upregulate ABCA1 Expression in a Model of Alzheimer’s Disease

2015 ◽  
Vol 1120-1121 ◽  
pp. 821-825
Author(s):  
Ke Xu ◽  
Xiong Zhang ◽  
Li Yu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholesterol Metabolism ◽  
Protein Levels ◽  
Atp Binding Cassette Transporter ◽  
Model Of Alzheimer’S Disease ◽  
Abca1 Expression ◽  
Underlying Mechanisms ◽  
Calcineurin Activity

Cholesterol metabolism plays an important role in pathogenesis of Alzheimer’s disease (AD). Curcumin has been reported to decrease cholesterol in serum through increasing the cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) expression, but the underlying mechanisms are not fully understand yet. To investigate the effects of curcumin on the activity of calcineurin and the expression of ABCA1 in vitro, N2a/APP695swe cells were treated with curcumin at 5 umol/L for 24 h, or with the calcineurin activity inhabitor CyclosporinA (CsA) at 0.5 umol/L for 48 h. Our findings showed that curcumin could increase the expression of the ABCA1 at mRNA and protein levels, furthermore, it could inhibit the calcineurin activity, CsA also could increase the expression of the ABCA1 at mRNA and protein levels. These findings suggest that curcumin may upregulate the expression of ABCA1 via inhibiting the calcineurin activity in N2a/APP695swe cells.

Sign in / Sign up

Export Citation Format

Share Document