ORCID Profile
0000-0002-9087-9041
Current Organisation
Shenzhen University
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Publisher: MDPI AG
Date: 27-10-2021
Abstract: Hydrogen peroxide (H2O2)-induced neuronal apoptosis is critical to the pathology of Alzheimer’s disease (AD) as well as other neurodegenerative diseases. The neuroprotective effects of apolipoprotein (ApoE) isoforms against apoptosis and the underlying mechanism remains controversial. Here, we have generated human cortical neurons from iPSCs and induced apoptosis with H2O2. We show that ApoE2 and ApoE3 pretreatments significantly attenuate neuronal apoptosis, whereas ApoE4 has no neuroprotective effect and higher concentrations of ApoE4 even display toxic effect. We further identify that ApoE2 and ApoE3 regulate Akt/FoxO3a/Bim signaling pathway in the presence of H2O2. We propose that ApoE alleviates H2O2-induced apoptosis in human iPSC-derived neuronal culture in an isoform specific manner. Our results provide an alternative mechanistic explanation on how ApoE isoforms influence the risk of AD onset as well as a promising therapeutic target for diseases involving neuronal apoptosis in the central nervous system.
Publisher: MDPI AG
Date: 21-07-2022
DOI: 10.3390/IJMS23148035
Abstract: Parkinson’s disease (PD) is characterized by the presence of Lewy bodies caused by α-synuclein. The imbalance of zinc homeostasis is a major cause of PD, promoting α-synuclein accumulation. ATP13A2, a transporter found in acidic vesicles, plays an important role in Zn2+ homeostasis and is highly expressed in Lewy bodies in PD-surviving neurons. ATP13A2 is involved in the transport of zinc ions in lysosomes and exosomes and inhibits the aggregation of α-synuclein. However, the potential mechanism underlying the regulation of zinc homeostasis and α-synuclein accumulation by ATP13A2 remains unexplored. We used α-synuclein-GFP transgenic mice and HEK293 α-synuclein-DsRed cell line as models. The spatial exploration behavior of mice was significantly reduced, and phosphorylation levels of α-synuclein increased upon high Zn2+ treatment. High Zn2+ also inhibited the autophagy pathway by reducing LAMP2a levels and changing the expression of LC3 and P62, by reducing mitochondrial membrane potential and increasing the expression of cytochrom C, and by activating the ERK/P38 apoptosis signaling pathway, ultimately leading to increased caspase 3 levels. These protein changes were reversed after ATP13A2 overexpression, whereas ATP13A2 knockout exacerbated α-synuclein phosphorylation levels. These results suggest that ATP13A2 may have a protective effect on Zn2+-induced abnormal aggregation of α-synuclein, lysosomal dysfunction, and apoptosis.
Publisher: Springer Science and Business Media LLC
Date: 12-02-2021
DOI: 10.1038/S42003-021-01722-0
Abstract: The dysregulation of gene dosage due to duplication or haploinsufficiency is a major cause of autosomal dominant diseases such as Alzheimer’s disease. However, there is currently no rapid and efficient method for manipulating gene dosage in a human model system such as human induced pluripotent stem cells (iPSCs). Here, we demonstrate a simple and precise method to simultaneously generate iPSC lines with different gene dosages using paired Cas9 nickases. We first generate a Cas9 nickase variant with broader protospacer-adjacent motif specificity to expand the targetability of double-nicking–mediated genome editing. As a proof-of-concept study, we examine the gene dosage effects on an Alzheimer’s disease patient-derived iPSC line that carries three copies of APP ( amyloid precursor protein ). This method enables the rapid and simultaneous generation of iPSC lines with monoallelic, biallelic, or triallelic knockout of APP . The cortical neurons generated from isogenically corrected iPSCs exhibit gene dosage-dependent correction of disease-associated phenotypes of amyloid-beta secretion and Tau hyperphosphorylation. Thus, the rapid generation of iPSCs with different gene dosages using our method described herein can be a useful model system for investigating disease mechanisms and therapeutic development.
Publisher: American Chemical Society (ACS)
Date: 27-05-2021
Publisher: Frontiers Media SA
Date: 12-06-2014
Publisher: Frontiers Media SA
Date: 15-04-2021
DOI: 10.3389/FNAGI.2021.660249
Abstract: Alzheimer’s disease (AD) is a type of neurodegenerative disease that is associated with the accumulation of amyloid plaques. Increasing non-amyloidogenic processing and/or manipulating amyloid precursor protein signaling could reduce AD amyloid pathology and cognitive impairment. D -penicillamine (D-Pen) is a water-soluble metal chelator and can reduce the aggregation of amyloid-β (Aβ) with metals in vitro . However, the potential mechanism of D-Pen for treating neurodegenerative disorders remains unexplored. In here, a novel type of chitosan-based hydrogel to carry D-Pen was designed and the D-Pen-CS/β-glycerophosphate hydrogel were characterized by scanning electron microscopy and HPLC. Behavior tests investigated the learning and memory levels of APP/PS1 mice treated through the D-Pen hydrogel nasal delivery. In vivo and in vitro findings showed that nasal delivery of D-Pen-CS/β-GP hydrogel had properly chelated metal ions that reduced Aβ deposition. Furthermore, D-Pen mainly regulated A disintegrin and metalloprotease 10 (ADAM10) expression via melatonin receptor 1 (MTNR1α) and the downstream PKA/ERK/CREB pathway. The present data demonstrated D-Pen significantly improved the cognitive ability of APP/PS1 mice and reduced Aβ generation through activating ADAM10 and accelerating non-amyloidogenic processing. Hence, these findings indicate the potential of D-Pen as a promising agent for treating AD.
Publisher: Wiley
Date: 25-04-2011
DOI: 10.1002/HIPO.20767
Abstract: It is well-known that zinc deficiency leads to neuronal death in the brain. Here we tested the hypothesis that changes in the TrkB signaling pathway are involved in hippoc al neuronal apoptosis of suckling offspring with maternal zinc deficiency. Postpartum mice were fed a zinc-deficient (0.85 ppm) diet and their offspring were used as a lactational zinc deficiency mouse model. At P7, P14, and P21, changes in hippoc al neuronal apoptosis were assessed by Nissl and TUNEL staining. BDNF levels and TrkB neurotrophic signaling were examined using immunoblotting assay. Lactational zinc deficiency resulted in lower levels of p-TrkB and p-ERK, and higher levels of Bax/Bcl-2 and caspase-3 in the hippoc us, suggesting that zinc deficiency-induced low levels of TrkB phosphorylation would abrogate the downstream ERK signaling pathway, leading to hippoc al neuronal apoptosis. Most interestingly, our data showed that the activity of Src, a key molecule for zinc-induced TrkB activation through the BDNF-independent pathway, was inhibited significantly, and the expression levels of BDNF were significantly increased in the hippoc us of suckling mice. The present data indicate that zinc depletion-induced hippoc al neuronal apoptosis is likely through modulation of the TrkB neurotrophic signaling pathway by a BDNF-independent and Src-dependent mechanism, whereas higher expression of BDNF is considered as a protective response, which cannot fully compensate for the injury caused by maternal zinc deficiency.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.AUTNEU.2008.04.002
Abstract: The superior cervical ganglion (SCG) neurons contain a considerable amount of zinc ions, but little is known about the zinc homeostasis in the SCG. It is known that zinc transporter 7 (ZnT7, Slc30a7), a member of the Slc30 ZnT family, is involved in mobilizing zinc ions from the cytoplasm into the Golgi apparatus. In the present study, we examined the expression and localization of ZnT7 and labile zinc ions in the mouse SCG using immunohistochemistry, Western blot and in vivo zinc selenium autometallography (AMG). Our immunohistochemical analysis revealed that the ZnT7 immunoreactivity in the SCG neurons was predominately present in the perinuclear region of the neurons, suggesting an affiliation to the Golgi apparatus. The Western blot results verified that ZnT7 protein was expressed in the mouse SCGs. The AMG reaction product was shown to have a similar distribution as ZnT7 immunoreactivity. These observations support the notion that ZnT7 may participate in zinc transport, storage, and incorporation of zinc into zinc-binding proteins in the Golgi apparatus of mouse SCG neurons.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.NBD.2015.06.016
Abstract: The pathological role of zinc in Alzheimer's disease (AD) is not yet fully elucidated, but there is strong evidence that zinc homeostasis is impaired in the AD brain and that this contributes to disease pathogenesis. In this study we examined the effects of zinc on the proteolysis of synthetic Apolipoprotein E (ApoE), a protein whose allelic variants differentially contribute to the onset rogression of disease. We have demonstrated that zinc promotes the proteolysis (using plasma kallikrein, thrombin and chymotrypsin) of synthetic ApoE in an isoform-specific way (E4>E2 and E3), resulting in more ApoE fragments, particularly for ApoE4. In the absence of exogenous proteases there was no effect of metal modulation on either lipidated or non-lipidated ApoE isoforms. Thus, increased zinc in the complex milieu of the ageing and AD brain could reduce the level of normal full-length ApoE and increase other forms that are involved in neurodegeneration. We further examined human plasma s les from people with different ApoE genotypes. Consistent with previous studies, plasma ApoE levels varied according to different genotypes, with ApoE2 carriers showing the highest total ApoE levels and ApoE4 carriers the lowest. The levels of plasma ApoE were not affected by either the addition of exogenous metals (copper, zinc or iron) or by chelation. Taken together, our study reveals that zinc may contribute to the pathogenesis of AD by affecting the proteolysis of ApoE, which to some extent explains why APOE4 carriers are more susceptible to AD.
Publisher: MDPI AG
Date: 25-06-2021
DOI: 10.3390/IJMS22136842
Abstract: Copper (Cu) has been implicated in the progression of Alzheimer’s disease (AD), and aggregation of Cu and amyloid β peptide (Aβ) are considered key pathological features of AD. Metal chelators are considered to be potential therapeutic agents for AD because of their capacity to reduce metal ion-induced Aβ aggregation through the regulation of metal ion distribution. Here, we used phage display technology to screen, synthesize, and evaluate a novel Cu(II)-binding peptide that specifically blocked Cu-triggered Aβ aggregation. The Cu(II)-binding peptide (S-A-Q-I-A-P-H, PCu) identified from the phage display heptapeptide library was used to explore the mechanism of PCu inhibition of Cu2+-mediated Aβ aggregation and Aβ production. In vitro experiments revealed that PCu directly inhibited Cu2+-mediated Aβ aggregation and regulated copper levels to reduce biological toxicity. Furthermore, PCu reduced the production of Aβ by inhibiting Cu2+-induced BACE1 expression and improving Cu(II)-mediated cell oxidative damage. Cell culture experiments further demonstrated that PCu had relatively low toxicity. This Cu(II)-binding peptide that we have identified using phage display technology provides a potential therapeutic approach to prevent or treat AD.
Publisher: Springer Science and Business Media LLC
Date: 07-2010
DOI: 10.1007/S12640-010-9206-Y
Abstract: Many studies have shown that zinc deficiency not only retards growth, but also affects several brain functions, including learning and memory. However, the underlying mechanism of impaired hippoc us-dependent learning and memory under zinc deficiency is poorly understood. In this study, young mice were fed a zinc-deficient diet (0.85 ppm) for 5 weeks. Morris water maze result showed that zinc deficiency results in spatial learning impairment. We then examined whether zinc depletion-induced learning and memory defects are associated with changes in signaling molecules essential for the expression of long-term potentiation. Immunoblot results showed that the protein levels of calmodulin (CaM), phosphorylated CaM-dependent protein kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (CREB) were significantly reduced, whereas the total protein levels of CaMKII and CREB did not change in the zinc-deficient hippoc us. Thus, we provide a previously unrecognized mechanism whereby zinc deficiency impairs hippoc al learning and memory, at least in part, through disruption of the CaM/CaMKII/CREB signaling pathway.
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