Alzheimer’s disease (AD) is characterized by distinct tissue changes associated with accumulation of extracellular amyloid-beta (Aβ) peptides, and intracellular deposits of phosphorylated Tau (p-tau). There is a clear need to develop 3D AD model for alternative to animal test since current rodent model does not recapitulate complex human AD physiopathology. Here we report on organoid-grafted neurovascular unit (NUV) using 1) spheroid using APP-mutated neuro-progenitor cell and 2) endothelial-based blood brain barrier (BBB) against extracellular matrix. The construct was validated with AD pathology generation and further treatment with β- or γ-secretase inhibitors shows the decrease of Aβ. This paper demonstrates the potential utility of a membrane-free in vitro cortical spheroid tissue construct with BBB in a high throughput platform to model AD.
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Nontoxic amphiphilic carbon dots as promising drug nanocarriers across the blood–brain barrier and inhibitors of β-amyloid
The blood–brain barrier (BBB) is a main obstacle for drug delivery targeting the central nervous system (CNS) and treating Alzheimer's disease (AD). In order to enhance the efficiency of drug delivery without harming the BBB integrity, nanoparticle-mediated drug delivery has become a popular therapeutic strategy. Carbon dots (CDs) are one of the most promising and novel nanocarriers. In this study, amphiphilic yellow-emissive CDs (Y-CDs) were synthesized with an ultrasonication-mediated methodology using citric acid and o -phenylenediamine with a size of 3 nm that emit an excitation-independent yellow photoluminescence (PL). The content of primary amine and carboxyl groups on CDs was measured as 6.12 × 10 −5 and 8.13 × 10 −3 mmol mg −1 , respectively, indicating the potential for small-molecule drug loading through bioconjugation. Confocal image analyses revealed that Y-CDs crossed the BBB of 5-day old wild-type zebrafish, most probably by passive diffusion due to the amphiphilicity of Y-CDs. And the amphiphilicity and BBB penetration ability didn't change when Y-CDs were coated with different hydrophilic molecules. Furthermore, Y-CDs were observed to enter cells to inhibit the overexpression of human amyloid precursor protein (APP) and β-amyloid (Aβ) which is a major factor responsible for AD pathology. Therefore, data suggest that Y-CDs have a great potential as nontoxic nanocarriers for drug delivery towards the CNS as well as a promising inhibiting agent of Aβ-related pathology of the AD.
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- Award ID(s):
- 1809060
- PAR ID:
- 10157865
- Date Published:
- Journal Name:
- Nanoscale
- Volume:
- 11
- Issue:
- 46
- ISSN:
- 2040-3364
- Page Range / eLocation ID:
- 22387 to 22397
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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