The combination of exercise training and α-lipoic acid treatment has therapeutic effects on the pathogenic phenotypes of Alzheimer's disease in NSE/APPsw-transgenic mice

Objective Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by aggregation of amyloid-β (Aβ) peptides. Reduction of progressive accumulation of Aβ will delay the progression of AD. As a main digestive organelles in cells, lysosome is crucial to clear the harmful proteins from extracellular and intracellular. Recent evidences have shown that exercise improves cognitive function of AD, but the reason is not very clear. This manuscript is to study the effect of long-term running exercise training on lysosomal function in mouse brain and explore its relationship with the progress of Alzheimer’s disease. Methods the APP/PSEN1 transgenic mice were used as the AD model to examine the relationship between AD, exercise and lysosomes. The mice were trained on a treadmill from the 5 months old, 60 min/day and 5 days/week for 5 months. The Lashley water maze and the novel object recognition test were used to estimate the cognitive ability of the mice; the balance beam and the rotating rod experiment were used to estimate motor coordination. The Aβ accumulation was measured with brain section and immunochemistry. The effects of long-term exercise on lysosomal function of cerebral cortex, striatum and hippocampus were measured. Among them, the autophagy/lysosome associated proteins level was determined by Western blot and the autophagy vacuoles and lysosome were observed through electron microscope. TFEB nuclear translocation was determined by Western blot and Immunofluorescence. The transcription of the TFEB-regulating genes were determined by quantitative PCR (qPCR). Results Long-term exercise improved the cognitive ability and physical coordination of AD transgenic mice. Exercise reduced Aβ accumulation through increase the clearance of Aβ and affected little on the production of Aβ. Exercise, not only increased the colocalization of lysosomes with Aβ, but also increased the mature type of lysosomal protease cathepsin D and cathepsin L. In the meanwhile, exercise promoted the nuclear translocation of TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy, and increased the transcription of genes associated with the biogenesis of lysosome. Conclusions Long-term exercise training delays the progress of Alzheimer's disease through activating function of lysosome and enhancing the biogenesis of lysosome. Exercise may be a therapeutic approach for the treatment of Alzheimer's disease.

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Faculty Opinions recommendation of Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1146910.604008 ◽

2009 ◽

Author(s):

Mark A Smith ◽

Bo Su

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Selective Reduction

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Synthesis of a Novel Curcumin Derivative as a Potential Imaging Probe in Alzheimer’s Disease Imaging

Current Alzheimer Research ◽

10.2174/1567205016666190816130516 ◽

2019 ◽

Vol 16 (8) ◽

pp. 723-731 ◽

Cited By ~ 1

Author(s):

Alexander Sturzu ◽

Sumbla Sheikh ◽

Hubert Kalbacher ◽

Thomas Nägele ◽

Christopher Weidenmaier ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Flow Cytometry ◽

Transgenic Mice ◽

Ex Vivo ◽

Amyloid Plaques ◽

Laser Scanning Microscopy ◽

Β Amyloid ◽

Curcumin Derivative

Background: Curcumin has been of interest in the field of Alzheimer’s disease. Early studies on transgenic mice showed promising results in the reduction of amyloid plaques.However, curcumin is very poorly soluble in aqueous solutions and not easily accessible to coupling as it contains only phenolic groups as potential coupling sites. For these reasons only few imaging studies using curcumin bound as an ester were performed and curcumin is mainly used as nutritional supplement. Methods: In the present study we produced an aminoethyl ether derivative of curcumin using a nucleophilic substitution reaction. This is a small modification and should not impact the properties of curcumin while introducing an easily accessible reactive amino group. This novel compound could be used to couple curcumin to other molecules using the standard methods of peptide synthesis. We studied the aminoethyl-curcumin compound and a tripeptide carrying this aminoethyl-curcumin and the fluorescent dye fluorescein (FITC-curcumin) in vitro on cell culture using confocal laser scanning microscopy and flow cytometry. Then these two substances were tested ex vivo on brain sections prepared from transgenic mice depicting Alzheimer-like β-amyloid plaques. Results: In the in vitro CLSM microscopy and flow cytometry experiments we found dot-like unspecific uptake and only slight cytotoxicity correlating with this uptake. As these measurements were optimized for the use of fluorescein as dye we found that the curcumin at 488nm fluorescence excitation was not strong enough to use it as a fluorescence marker in these applications. In the ex vivo sections CLSM experiments both the aminoethyl-curcumin and the FITC-curcumin peptide bound specifically to β- amyloid plaques. Conclusion: In conclusion we successfully produced a novel curcumin derivative which could easily be coupled to other imaging or therapeutic molecules as a sensor for amyloid plaques.

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MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

Current Neurovascular Research ◽

10.2174/1567202617666200128141938 ◽

2020 ◽

Vol 17 (1) ◽

pp. 93-101 ◽

Cited By ~ 3

Author(s):

Dan Wang ◽

Zhifu Fei ◽

Song Luo ◽

Hai Wang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Western Blot ◽

Mrna Expression ◽

Cognitive Deficits ◽

Protein Levels ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

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Therapeutic effects of non-saponin fraction with rich polysaccharide from Korean red ginseng on aging and Alzheimer’s disease

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2020.12.454 ◽

2021 ◽

Author(s):

Soo Jung Shin ◽

Yunkwon Nam ◽

Yong Ho Park ◽

Min-Jeong Kim ◽

Eunbeen Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Effects ◽

Red Ginseng ◽

Korean Red Ginseng ◽

Saponin Fraction

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Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Cells ◽

10.3390/cells10040779 ◽

2021 ◽

Vol 10 (4) ◽

pp. 779

Author(s):

Pradeep K. Shukla ◽

David F. Delotterie ◽

Jianfeng Xiao ◽

Joseph F. Pierre ◽

RadhaKrishna Rao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Gut Microbiota ◽

Transgenic Mice ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Gut Barrier Function ◽

Elevated Expression ◽

5Xfad Mice

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

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