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Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid-beta, tau hyperphosphorylation and neurotrophic dysfunction.

ABSTRACT: Background:Targeted proteinopathy is involved in creating pharmacological agents that protect against Alzheimer disease (AD). Cornel iridoid glycoside (CIG) is an effective component derived from Cornus officinalis. The present study aimed to determine the effects of CIG on ?-amyloid (A?) and tau pathology and the underlying mechanisms in APP/PS1/tau triple transgenic (3×Tg) model mice. Methods:We intragastrically administered 16-month-old 3×Tg mice with CIG (100 and 200 mg/kg) daily for two months. Learning and memory abilities were determined using the Morris water maze (MWM) and object recognition tests (ORT). Amyloid plaques and A?40/42 and the expression of related proteins in the cerebral cortex and hippocampus of mice was determined by western blotting. Results:CIG improved learning and memory impairment in 3×Tg model mice, decreased amyloid plaque deposition, A?40/42 and the expression of full-length amyloid precursor protein, and increased levels of ADAM-10 (?-secretase), neprilysin (NEP), and insulin degrading enzyme (IDE) in the brains of the model mice. CIG also reduced tau hyperphosphorylation, and elevated phosphorylation level of GSK-3? at Ser9 and methylation of PP2A catalytic subunit C in the model mice. Moreover, CIG increased the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-responsive element binding protein (p-CREB) in the brain of 3×Tg mice. Conclusions:CIG ameliorated learning and memory deficit via reducing A? content and, tau hyperphosphorylation and increasing neurotrophic factors in the brain of 3×Tg mice. These results suggest that CIG may be beneficial for AD therapy.

SUBMITTER: Yang C

PROVIDER: S-EPMC7186687 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid-beta, tau hyperphosphorylation and neurotrophic dysfunction.

Yang Cuicui C Bao Xunjie X Zhang Li L Li Yali Y Li Lin L Zhang Lan L

Annals of translational medicine 20200301 6

<h4>Background</h4>Targeted proteinopathy is involved in creating pharmacological agents that protect against Alzheimer disease (AD). Cornel iridoid glycoside (CIG) is an effective component derived from <i>Cornus officinalis</i>. The present study aimed to determine the effects of CIG on β-amyloid (Aβ) and tau pathology and the underlying mechanisms in APP/PS1/tau triple transgenic (3×Tg) model mice.<h4>Methods</h4>We intragastrically administered 16-month-old 3×Tg mice with CIG (100 and 200 mg ...[more]

PMID: 32355772

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Project description:BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder strongly correlated with a dysfunctional immune system. Our previous results demonstrated that inactivated influenza vaccine (IIV) facilitates hippocampal neurogenesis and blocks lipopolysaccharide (LPS)-induced cognitive impairment. However, whether IIV improves cognitive deficits in an AD mouse model remains unclear. In addition, early interventions in AD have been encouraged in recent years. Here, we investigated whether IIV immunization at the preclinical stage of AD alters the brain pathology and cognitive deficits in an APP/ PS1 mouse model.MethodsWe assessed spatial learning and memory using Morris water maze (MWM). The brain ?-amyloid (A?) plaque burden and activated microglia were investigated by immunohistochemistry. Furthermore, flow cytometry was utilized to analyze the proportions of Treg cells in the spleen. A cytokine antibody array was performed to measure the alteration of cytokines in the brain and peripheral immune system.ResultsFive IIV immunizations activated microglia, reduced the A? burden and improved the cognitive impairment. Simultaneously, the IIV-induced immune response broke peripheral immunosuppression by reducing Foxp3+ regulatory T cell (Treg) activities, whereas the restoration of Treg level in the periphery using all-trans retinoic acid (ATRA) blunted the protective effects of IIV on A? burden and cognitive functions. Interestingly, IIV immunization might increase proinflammatory and anti-inflammatory cytokine expression in the brain of APP/PS1 mice, enhanced microglial activation, and enhanced the clustering and phagocytosis of A?, thereby creating new homeostasis in the disordered immune microenvironment.ConclusionsAltogether, our results suggest that early multiple IIV immunizations exert a beneficial immunomodulatory effect in APP/PS1 mice by breaking Treg-mediated systemic immune tolerance, maintaining the activation of microglia and removing of A? plaques, eventually improving cognitive deficits.

Project description:BackgroundAmyloid beta (Aβ) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied.MethodsTo genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP).ResultsIt is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aβ production in the perforant path and levels of soluble Aβ and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and β-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway.ConclusionsOur findings demonstrate that perforant path NgR plays an important role in regulating APP/Aβ level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.

Dataset Information

Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid-beta, tau hyperphosphorylation and neurotrophic dysfunction.

Publications

Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid-beta, tau hyperphosphorylation and neurotrophic dysfunction.

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