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Abnormalities of plasma cytokines and spleen in senile APP/PS1/Tau transgenic mouse model.

ABSTRACT: The blood-based diagnosis has a potential to provide an alternative approach for easy diagnosis of Alzheimer's disease (AD) with less invasiveness and low-cost. However, present blood-based AD diagnosis mainly focuses on measuring the plasma A? level because no other biomarkers are found to possess evident transport mechanisms to pass the blood-brain barrier. In order to avoid diagnosing non-demented individuals with A? abnormality, finding additional biomarkers to supplement plasma A? is essential. In this study, we introduce potential neurodegenerative biomarkers for blood-based diagnosis. We observed severe splenomegaly and structural destruction in the spleen with significantly decreased B lymphocytes in senile APPswe, PS1M146V and TauP301L transgenic mice. We also found that inflammatory cytokines associated with splenic dysfunction were altered in the plasma of these mice. These findings suggest potential involvement of the splenic dysfunction in AD and the importance of biomarker level alterations in the plasma as putative diagnostic targets for AD.

SUBMITTER: Yang SH

PROVIDER: S-EPMC4621607 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Abnormalities of plasma cytokines and spleen in senile APP/PS1/Tau transgenic mouse model.

Yang Seung-Hoon SH Kim Jiyoon J Lee Michael Jisoo MJ Kim YoungSoo Y

Scientific reports 20151027

The blood-based diagnosis has a potential to provide an alternative approach for easy diagnosis of Alzheimer's disease (AD) with less invasiveness and low-cost. However, present blood-based AD diagnosis mainly focuses on measuring the plasma Aβ level because no other biomarkers are found to possess evident transport mechanisms to pass the blood-brain barrier. In order to avoid diagnosing non-demented individuals with Aβ abnormality, finding additional biomarkers to supplement plasma Aβ is essent ...[more]

PMID: 26503550

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Project description:Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both A? level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both A? levels and Tau hyperphosphorylation. SH-SY5Y and CHO-APP/BACE1 cells and primary astrocytes were used in cell-based assays. APP/PS1 transgenic mice [B6C3-Tg(APPswe, PS1dE9)] were administered THA (300 mg·kg-1·d-1, ig) for 100 d. After the administration was completed, the learning ability of the mice was detected using a Morris water maze (MWM) assay; immunofluorescence staining, Congo red staining and Thioflavine S staining were used to detect the senile plaques in the brains of the mice. ELISA was used to evaluate A? and sAPP? contents, and Western blotting and RT-PCR were used to investigate the relevant signaling pathway regulation in response to THA treatment. In SH-SY5Y cells, TH? (1, 10, 20 ?g/mL) significantly stimulated PI3K/AKT/mTOR and AMPK/raptor/mTOR signaling-mediated autophagy in the promotion of A? clearance as both a PI3K inhibitor and an AMPK indirect activator, and restrained A? production as a suppressor against PERK/eIF2?-mediated BACE1 expression. Additionally, THA functioned as a GSK3? inhibitor with an IC50 of 1.32±0.85 ?g/mL, repressing Tau hyperphosphorylation. Similar effects on A? accumulation and Tau hyperphosphorylation were observed in APP/PS1 transgenic mice treated with THA. Furthermore, administration of THA effectively improved the learning ability of APP/PS1 transgenic mice, and markedly reduced the number of senile plaques in their hippocampus and cortex. The results highlight the potential of the natural product THA for the treatment of AD.

Project description:BackgroundA great body of evidence suggests that there are retinal functional and structural changes that occur in Alzheimer's disease (AD). However, whether such changes are primary or secondary remains to be elucidated. We studied a range of retinal functional and structural parameters in association with AD- specific pathophysiological markers in the double transgenic APP/PS1 and control mice across age.MethodsElectroretinogram (ERG) and optical coherence tomography (OCT) was performed in APP/PS1 and wild type (WT) control mice every 3 months from 3 to 12?months of age. For functional assessment, the a- and b-wave of the ERG, amplitude of oscillatory potentials (OP) and the positive scotopic threshold response (pSTR) were quantified at each time point. For structural assessment, the inner and outer retinal thickness was segmented and measured from OCT scans. Episodic memory was evaluated at 6, 9 and 12?months of age using the novel object recognition test. Amyloid beta (A?) distribution in the hippocampus and the retina were visualised at 3, 6 and 12?months of age. Inter- and intra- group analysis was performed to study rate of change for each parameter between the two groups.ResultsInter-group analysis revealed a significant difference in b-wave and OPs of APP/PS1 compared to WT controls starting from 3?months (p?<?0.001). There was also a significant difference in the amplitude of pSTR between the two groups starting from 6?months (p?<?0.001). Furthermore, a significant difference in the inner retinal thickness, between the two groups, was observed starting from 9?months (p?<?0.001).ConclusionsWe observed an age-related decline in retinal functional and structural parameters in both APP/PS1 and WT controls, however, inter-group analysis revealed that inner retinal functional and structural decline is exacerbated in APP/PS1 mice, and that retinal functional changes precede structural changes in this strain. Further studies are required to confirm whether such phenomenon occurs in humans and if studying retinal functional changes can aid-in early assessment of AD.

Dataset Information

Abnormalities of plasma cytokines and spleen in senile APP/PS1/Tau transgenic mouse model.

Publications

Abnormalities of plasma cytokines and spleen in senile APP/PS1/Tau transgenic mouse model.

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