CAS procedure Liu Ruitian / Lu Shuai \”AFM\”: will release \”Do not eat me\” signal of polymeric nanoparticles, is expected to be used to treat Alzheimer\’s

Alzheimer\’s disease (Alzheimer\’s disease, AD) is a degenerative disease of the central nervous system, is the most common type of dementia, mainly by progressive memory impairment, cognitive impairment and languages neurological disorders, psychiatric symptoms, typical pathological feature is extracellular amyloid beta] (amyloid-β, Aβ plaques) formed by deposition of senile plaques, intracellular neurofibrillary tangles and brain atrophy. Since the blood-brain barrier (Blood-Brain Barrier, BBB) hinders most drugs to reach the brain, brain effective drug delivery has been a major challenge for AD and other brain diseases. In order to improve BBB permeability, scientists have developed as BBB penetrating peptides (CRTIGPSVC, CRT), selective targeting CD47 glycoprotein modulators and microglia (Necrostatin-1s, Nec-1s), etc. endogenous transport mechanisms; however, penetrating peptide low transport capacity, Nec-1s poor water solubility and low bioavailability and brain defects brought great difficulties to the study. Recently, Institute of Process Engineering Liu Ruitian and Lu Shuai team developed a new type of poly (lactic acid – glycolic acid) (PLGA) copolymer nanoparticles (CRT-CD47-NP-Nec-1s), through which reactive oxygen species (ROS) responsive to the phenylboronic acid ester bond conjugated CD47 extracellular domain, [ 123] show, \”Do not eat me\” signal , and CRT and Nec-1s wrapped in one. Found high levels of mouse brain ROS cause release of CD47 nanoparticles, resulting granules effectively resident microglial phagocytosis, engulfed Nec-1s may be adjusted to pathological advantageous microglia state, reduce Aβ plaque burden, the proliferation of microglia and astrocytes proliferation, reduce oxidative stress and cytokines AD brain of mice, and ultimately reduce synaptic loss and cognitive impairment therapeutic effect. The study is the first demonstration, the condition for the release of \”Do not eat me\” CD47 signal significantly promoted microglial cells targeted drug delivery, worthy of further research and development of drugs to treat AD. This studyEntitled to the results of \”A Conditionally Releasable\” Do not Eat Me \”CD47 Signal Facilitates Microglia-Targeted Drug Delivery for the Treatment of Alzheimer\’s Disease\” published in the paper \” Advanced Functional Materials \”. As shown, the first wrapping Nec-1s into the copolymer by NPs nanoprecipitation 1, CRT and then respectively NPs surface CD47, and benzene boronic acid conjugate prepared CRT-CD47-NP-Nec- 1s, TEM spectra showed CRT-CD47-NP-Nec-1s from about 70 nm uniform spherical size. 中科院过程所刘瑞田/卢帅《AFM》:会释放“不要吃我”信号的聚合物纳米粒子, 有望用于治疗老年痴呆

中科院过程所刘瑞田/卢帅《AFM》:会释放“不要吃我”信号的聚合物纳米粒子, 有望用于治疗老年痴呆 FIG 1. CRT-CD47-NP-Nec-1s a schematic view of the transport and AD mice affects the brain microglia and neurons of the
To investigate the CRT-CD47 -NP-Nec-1s Effect on memory and learning ability of AD mice subjected to a Morris water maze, Y maze test, and novel object discrimination experiments. Morris water maze training, NP-Nec-1s-, escape latency CRT-NP-Nec-1s- and CRT-CD47-NP-Nec-1s- experimental mice gradually reduced, wherein the CRT-NP-Nec- 1S- and CRT-CD47-NP-Nec-1s- experimental mice through the first target position significantly shortened, the number of crossing even more, and the longer target quadrant (FIG. 2A-D); Y-maze test in, CRT-NP-Nec-1s- and CRT-CD47-NP-Nec-1s- experimental mice in the novel arm longer residence times and more accessible; in novel object discrimination experiment, CRT-NP -Nec-1s- and CRT-CD47-NP-Nec-1s- novel object experimental mice exhibited higher discrimination index (FIG. 2E). The results showed that CRT-NP-Nec-1s and CRT-CD47-NP-Nec-1s significantly reduced memory and cognitive deficits in AD mouse and CRT-CD47-NP-Nec-1s most significant effect.
中科院过程所刘瑞田/卢帅《AFM》:会释放“不要吃我”信号的聚合物纳米粒子, 有望用于治疗老年痴呆 FIG. 2. CRT-CD47-NP-Nec-1s to save memory and cognition defects in AD mice
Researchers have investigated by immunohistochemistry using the NPs of AD Effect pathological features mice showed CRT-NP-Nec-1s- and CRT-CD47-NP-Nec-1s- Aβ plaque burden in the brain of mice in the experimental group significantly decreased (FIG. 3A, B), described CRT-CD47 -NP-Nec-1s effectively reduces the β-amyloid disease; and NP-Nec-1s, CRT-NP-Nec-1s and CRT-CD47-NP-Nec-1s markedly reduced AD mouse microglial stromal cell proliferation and proliferation of astrocytes (FIG. 3C-F). In addition, the study found CRT-NP-Nec-1s and CRT-CD47-NP-Nec-1s increases the GSH / GSSG ratio, thereby reducing oxidative stress in brain AD mice.
中科院过程所刘瑞田/卢帅《AFM》:会释放“不要吃我”信号的聚合物纳米粒子, 有望用于治疗老年痴呆 FIG. 3. CRT-CD47-NP-Nec-1s reduce β-amyloid lesions in AD mice, the proliferation of microglia and astrocytes proliferation
Nissl staining results showed that the number of CRT-NP-Nec-1s- nerve cell survival, and CRT-CD47-NP-Nec-1s- mouse brain CA1 area of ​​the experimental group was significantly increased (Figure 4A, B), Western blot results found, NP-Nec-1s-, hippocampus SYN CRT-NP-Nec-1s- and CRT-CD47-NP-Nec-1s- experimental mice and increased level of expression of PSD95, wherein the CRT-CD47-NP- Nec-1s effect is particularly significant (Figure 4C, D), therefore, CRT-CD47-NP-Nec-1s can repair damaged neurons, synaptic damage and loss improvement.
中科院过程所刘瑞田/卢帅《AFM》:会释放“不要吃我”信号的聚合物纳米粒子, 有望用于治疗老年痴呆 FIG. 4. CRT-CD47-NP-Nec-1s improve AD mice synaptic damage and loss of
In vitro results showed CRT-CD47-NP-Nec-1s reduced after Aβ treated BV2 cells Ch25h and transcript levels CST7 (Figure 5A, B), while the in vivo results show that, NP-Nec-1s, CRT-NP-Nec-1s and CRT-CD47 -NP-Nec-1s were significantly reduced in mice and Ch25h AD CST7 transcript levels (Figure 5C, D). The study also found that, CRT-CD47-NP-Nec-1s efficiently reduces expression (FIG. 5E-F) lysosomes in vivo AD MICE Cst7, indicating CRT-CD47-NP-Nec-1s can modulate small AD and generating murine RIPK1 Cst7 will microglia pathological state was adjusted to be beneficial
中科院过程所刘瑞田/卢帅《AFM》:会释放“不要吃我”信号的聚合物纳米粒子, 有望用于治疗老年痴呆 FIG. 5. CRT-CD47-NP-Nec-1s regulation pathological state advantageous to microglia [ 123]

Highlights Summary:

developed by the Institute of CRT-CD47-NP-Nec-1s by preventing phagocytic cells, effectively prolonging its circulation in blood half-life, and CD47 synergistically enhances CRT and its distribution in the brain, being swallowed Nec-1s may be adjusted pathological state advantageous to microglia, by reducing plaque burden and Aβ repair of damaged neurons to save the synaptic loss and cognitive impairment. This microglia targeted drug delivery nanoparticles are expected to be used to explore the role of microglia in AD pathogenesis is of great significance for the research and development of therapeutic AD drugs. The full text link: https: //doi.org/10.1002/adfm.201910691

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