ABSTRACT
Cleavage of Amyloid precursor protein (APP) by the ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting step in the production of amyloid-ß (Aß) synaptotoxins. The siRNA-mediated silencing to attenuate the expression of BACE1 to ameliorate cognitive dysfunction in mice had been investigated. To improve therapeutic gene delivery to the central nervous system, cationic copolymer poly(ethylene glycol)-b-poly[N-(N'-{N''-[N'''-(2-aminoethyl)-2-aminoethyl]-2-aminoethyl}-2-aminoethyl)aspartamide]-cholesterol was synthesized, then RVG29 and Tet1 peptides were exploited as ligands to construct a dual-targeting brain gene delivery polyion complex (Tet1/RVG29-PIC). The cell uptake of a coculture cell model showed that the Tet1/RVG29-PIC exhibited notable transport characteristics and possessed affinity towards nerve cells. In vivo transfection, Tet1/RVG29-PIC possessed the highest expression of luciferase in brain compared with that of RVG29-PIC or Tet1-PIC, which were 1.25 and 1.22 times respectively. Silence BACE1 expression using siRNA-expressing plasmid loaded Tet1/RVG29-PIC that improved behavioral deficits in the APP/PS1 mouse model, demonstrating the favorable brain delivery properties of Tet1/RVG29-PIC by synergistical engagement of GT1B and nicotinic acetylcholine receptors. Our results suggested that the nanoformulation has the potential to be exploited as a multistage-targeting gene vector for the CNS disease therapy.
Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Animals , Mice , Alzheimer Disease/genetics , Alzheimer Disease/therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Amyloid Precursor Protein Secretases/genetics , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Brain/metabolism , Mice, Transgenic , RNA, Small Interfering/metabolismABSTRACT
Low-carbon development requires joint efforts in terms of "carbon reduction" and "carbon sink increase." This study thus proposes a DICE-DSGE model for exploring the environmental and economic benefits of ocean carbon sinks and provides policy suggestions for marine economic development and carbon emission policy choices. The results are as follows: (1) while the economic benefits of heterogeneous technological shocks are apparent, the environmental benefits of carbon tax and carbon quota shocks are significant; (2) increasing the efficiency of ocean carbon sinks improves the environmental benefits of technological shocks as well as the output benefits of emission reduction tools, while increasing the share of marine output can improve both the economic benefits of technological shocks and the environmental benefits of emission reduction tools; and (3) ocean output proportion has the most considerable positive effect on social welfare, followed by marine total factor productivity (TFP). The correlation effect of ocean carbon sink efficiency is negative.
