How Does Self-Rated Health Vary as a Function of Cognitive Deficits in Adults with Mild Alzheimer's Disease?

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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Neuroprotective Effects of Fluoxetine on Molecular Markers of Circadian Rhythm, Cognitive Deficits, Oxidative Damage, and Biomarkers of Alzheimer’s Disease-Like Pathology Induced under Chronic Constant Light Regime in Wistar Rats

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.1c00238 ◽

2021 ◽

Author(s):

Ashish Sharma ◽

Ashu Mohammad ◽

Adesh K. Saini ◽

Rohit Goyal

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Rhythm ◽

Molecular Markers ◽

Oxidative Damage ◽

Cognitive Deficits ◽

Wistar Rats ◽

Light Regime ◽

Constant Light ◽

Neuroprotective Effects

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Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1510011112 ◽

2015 ◽

Vol 112 (38) ◽

pp. 11965-11970 ◽

Cited By ~ 64

Author(s):

Li Zhu ◽

Minghao Zhong ◽

Gregory A. Elder ◽

Mary Sano ◽

David M. Holtzman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Deficits ◽

Genetic Risk ◽

Primary Neurons ◽

Loss Of Function ◽

Sporadic Alzheimer’S Disease ◽

Postmortem Human Brain ◽

Apoe4 Allele ◽

Synaptojanin 1

The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.

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