Intraneuronal β-Amyloid Accumulation in the Amygdala Enhances Fear and Anxiety in Alzheimer's Disease Transgenic Mice

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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Comparison of Neurodegenerative Pathology in Transgenic Mice Overexpressing V717F β-Amyloid Precursor Protein and Alzheimer’s Disease

Journal of Neuroscience ◽

10.1523/jneurosci.16-18-05795.1996 ◽

1996 ◽

Vol 16 (18) ◽

pp. 5795-5811 ◽

Cited By ~ 261

Author(s):

Eliezer Masliah ◽

Abbyann Sisk ◽

Margaret Mallory ◽

Lennart Mucke ◽

Dale Schenk ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Amyloid Precursor Protein ◽

Precursor Protein ◽

Neurodegenerative Pathology ◽

Β Amyloid

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Elevated Aβ and Apolipoprotein E in AβPP Transgenic Mice and Its Relationship to Amyloid Accumulation in Alzheimer’s Disease

Molecular Medicine ◽

10.1007/bf03401785 ◽

2000 ◽

Vol 6 (5) ◽

pp. 430-439 ◽

Cited By ~ 47

Author(s):

Yu-Min Kuo ◽

Fiona Crawford ◽

Michael Mullan ◽

Tyler A. Kokjohn ◽

Mark R. Emmerling ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Apolipoprotein E ◽

Amyloid Accumulation

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Concomitant detection of β-amyloid peptides with N-terminal truncation and different C-terminal endings in cortical plaques from cases with Alzheimer's disease, senile monkeys and triple transgenic mice

Journal of Chemical Neuroanatomy ◽

10.1016/j.jchemneu.2010.03.006 ◽

2010 ◽

Vol 40 (1) ◽

pp. 82-92 ◽

Cited By ~ 18

Author(s):

Wolfgang Härtig ◽

Simone Goldhammer ◽

Ute Bauer ◽

Florian Wegner ◽

Oliver Wirths ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Amyloid Peptides ◽

Β Amyloid

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RIPK1 promotes inflammation and β-amyloid accumulation in Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1715241114 ◽

2017 ◽

Vol 114 (41) ◽

pp. 10813-10814 ◽

Cited By ~ 6

Author(s):

David C. Rubinsztein

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Accumulation ◽

Β Amyloid

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Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.749587 ◽

2021 ◽

Vol 15 ◽

Author(s):

Guimei Zhang ◽

Zicheng Wang ◽

Huiling Hu ◽

Meng Zhao ◽

Li Sun

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Interventions ◽

Tau Pathology ◽

Age Related ◽

Amyloid Accumulation ◽

Pathophysiological Role ◽

Inflammatory Drugs ◽

Β Amyloid

Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.

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