ORCID Profile
0000-0001-9428-0813
Current Organisation
Dalian Institute of Chemical Physics
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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: American Chemical Society (ACS)
Date: 27-05-2021
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: 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.
No related grants have been discovered for Xiaoyu Zhang.