A Novel, Multi-Target Natural Drug Candidate, Matrine, Improves Cognitive Deficits in Alzheimer’s Disease Transgenic Mice by Inhibiting Aβ Aggregation and Blocking the RAGE/Aβ Axis

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.

Download Full-text

Emodin inhibits aggregation of amyloid‐β peptide 1–42 and improves cognitive deficits in Alzheimer's disease transgenic mice

Journal of Neurochemistry ◽

10.1111/jnc.15156 ◽

2020 ◽

Author(s):

Lichun Wang ◽

Sitong Liu ◽

Jiaqi Xu ◽

Nobumoto Watanabe ◽

Kevin H. Mayo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Cognitive Deficits ◽

Amyloid Β ◽

Amyloid Β Peptide

Download Full-text

Yeast-Based Aβ1-15 Vaccine Elicits Strong Immunogenicity and Attenuates Neuropathology and Cognitive Deficits in Alzheimer’s Disease Transgenic Mice

Vaccines ◽

10.3390/vaccines8030351 ◽

2020 ◽

Vol 8 (3) ◽

pp. 351

Author(s):

Dong-qun Liu ◽

Shuai Lu ◽

Lun Zhang ◽

Ya-ru Huang ◽

Mei Ji ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Wall ◽

Transgenic Mice ◽

Cognitive Deficits ◽

Plaque Burden ◽

High Antibody ◽

Safety And Efficacy ◽

Antibody Titers ◽

Promising Treatment

Immunotherapy focusing on reducing the amyloid-beta (Aβ) burden is a promising treatment strategy for Alzheimer’s disease (AD). Many clinical studies on AD immunotherapies have failed due to low safety and efficacy, calling for a highly potent AD vaccine which induces sufficient antibody titer while avoiding side effects. Here, we designed a yeast-based vaccine Y-5A15 comprising five copies of Aβ1-15 displayed on the surface of yeast cell wall, and we subcutaneously immunized APP/PS1 mice three times. Our results demonstrated that the Y-5A15 remarkably enhanced the Aβ epitope immunogenicity and elicited high antibody titers against Aβ in AD mice. Importantly, Y-5A15 vaccination successfully reduced Aβ levels, plaque burden and glial activation, rescued synaptic deficits and significantly ameliorated memory and cognitive decline in APP/PS1 transgenic mice, suggesting that the yeast-based Aβ epitope vaccine has a promising potency for the treatment of AD.

Download Full-text