期刊
ACS APPLIED MATERIALS & INTERFACES
卷 7, 期 10, 页码 5650-5662出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.5b00915
关键词
Alzheimer's disease; protein aggregation; amyloid beta-protein; peptide inhibitor; self-assembly; nanoparticle
资金
- Natural Science Foundation of China [21376172, 21236005]
- High-Tech Research and Development Program of China from the Ministry of Science and Technology of China [2012AA020206]
- National Science Foundation [CBET-0952624, CBET-1158447]
- Directorate For Engineering [0952624] Funding Source: National Science Foundation
- Div Of Chem, Bioeng, Env, & Transp Sys [1158447] Funding Source: National Science Foundation
Aggregation of amyloid beta-protein (A beta) into amyloid,oligothers and fibrils is pathologiCally linked to AlZheimer's diSease (AD). Hence, the inhibition of A beta aggregation is essential for the prevention and treatment of A, but the development of potent agents capable of inhibiting A beta fibrillogenesis has posed significant challenges. Herein, we designed Ac-LVFFARK-NH2 (LK7) by incorporating two positively charged residues, R and K, into the central hydrophobic fragment of A beta 17-21 (LVFFA) and examined its inhibitory effect on A beta 42 aggregation and cytotcodcity by extensive.:physical, biophysical, and biological analyses. LK7 was observed to inhibit A beta 42 fibrillogenesis in a dose-dependent manner, but its strong self-assembly characteristic also resulted in high cytotoxicity. In order to prevent the cytotoXicity that resulted from the self-assembly of LK71 the peptide was then conjugated to the surface of poly(lactic-co-glycolic acid) (PLGA) nanopartides (NPs) to fabricate a nanosized inhibitor, LK7@PLGA-NPs. It was found that LK7@PLGA-NPs had little cytotoxicity because the self-assembly of the LK7 conjugated on the NPS was completely inhibited. Moreover, the NPs-based inhibitor showed remarkable inhibitory capability against A4342 aggregation and significantly alleviated its cytotoxicity at a low LK7@PLGA-NPs concentration of 20 fig/mL. At the :same peptide concentration, free LK7 showed little inhibitory effect. It is considered that several synergetic effects contributed to the strong inhibitory ability of LK7@PLGA-NP5, including the enhanced interactions between A1342 and LK7@PLGA,NPs, brought on by inhibiting LK7 self-assembly, restricting conformational changes of A beta 42, and thus redirecting A342 aggregation into unstructured, off-pathway aggregates. The working mechanisms of the inhibitory effects of LK7 and I,K7@PLGA-NP5 on A beta 42 aggregation were proposed based on experimental observations. This work provides new insights into the design and development of potent NPs-based inhibitors against A beta aggregation and cytotcodcity.
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