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Written by ︱ Sen Liu, edited by Jinfang Ge ︱ Sizhen Wang Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accounting for about 50-60% of all dementias [1 ]
.
Exosomes are a class of extracellular vesicles with a diameter of about 30-200 nm, which carry important genetic information such as mRNA, miRNA, and proteins, and can mediate information transfer and communication between cells [2]
.
Exosomes derived from bone marrow mesenchymal stem cells (BMSC-exos) are extracellular vesicles that can perform the function of bone marrow mesenchymal stem cells.
Disease research has shown a certain therapeutic effect [3-6]
.
It has been reported that the neuroinflammation and neuronal apoptosis of primary neurons in AD transgenic mice were significantly inhibited after mesenchymal stem cell-derived exosomes [7]
.
In addition, studies have found that intranasal administration of mesenchymal stem cell-derived exosomes can reduce inflammation and prevent abnormal neurogenesis and memory dysfunction after status epilepticus [8]
.
However, the mechanisms underlying the effects of BMSC-exos on neuroinflammation and cognitive decline in AD model animals have not been elucidated
.
On February 7, 2022, the team of Prof.
Jinfang Ge from School of Pharmacy, Anhui Medical University, and Prof.
Qingrong Xia from the Affiliated Psychological Hospital published a paper entitled "Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like" in the Journal of Neuroinflammation.
The article "mice by improving BDNF-related neuropathology" describes how BMSC-exos alleviates the decline of learning and memory in AD model mice, and proves that BMSC-exos can reduce neuroinflammation in AD mice and reduce pale powder in the brain.
The accumulation of protein and decrease the phosphorylation level of tau protein and promote neurogenesis
.
In order to study the effect of BMSC-exos on the cognitive ability of AD mice, the authors cultured in vitro and purified bone marrow mesenchymal stem cells by flow sorting system, extracted their exosomes, and injected streptozotocin into the lateral ventricle.
Methods The AD mouse model was established, and the distribution of BMSC-exos labeled with PKH-26 fluorescent dye was observed after injecting into the lateral ventricle of the mouse (Fig.
1)
.
The results showed that BMSC-exos administered by intracerebroventricular injection were able to diffuse to the hippocampus along with the cerebral circulation (Fig.
2)
.
Figure 1 Experiment flow chart (STZ: streptozotocin, OFT: open field test, NOR: novel object recognition test, Y-maze: Y-maze test, TST: tail suspension test) (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Figure 2 BMSC-exos injection site and tracer (Source: Sen Liu et al.
, J Neuroinflammation.
2022) The authors observed the neuropsychiatric effects of BMSC-exos in AD mice through a classical neurobehavioral approach The results showed that compared with the model group, the AD model mice showed a significant increase in the novel object preference index in the novel object recognition experiment after the lateral ventricle injection of BMSC-exos, and the novel arm preference index in the Y-maze experiment also increased.
uptrend (Figure 3)
.
Figure 3 The effect of BMSC-exos on the behavioral performance of AD mice in NOR and Y-maze (Source: Sen Liu et al.
, J Neuroinflammation.
2022) The abnormal activation of glial cells is closely related to neuroinflammation, the authors further Immunofluorescence, Western blot and qPCR techniques were used to detect the expression levels of inflammatory factors and the activation of glial cells in the hippocampus of mice
.
The results showed that injection of BMSC-exos into the lateral ventricle could reduce the protein and mRNA expression levels of inflammatory factors IL-1β, IL-6 and TNF-α in the hippocampus of AD mice (Fig.
4), and inhibited the activation of microglia.
(Fig.
5), reduced neuroinflammation
.
Figure 4 BMSC-exos reduced the expression levels of IL-1β, IL-6 and TNF-α protein and mRNA in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Figure 5 BMSC-exos Inhibits the activation of microglia in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Microglia are involved in the clearance process of amyloid in the brain, and microglia in the inflammatory state Cells lose phagocytosis and promote neuroinflammation, which simultaneously promotes amyloid accumulation and indirectly leads to abnormal phosphorylation of Tau protein [9]
.
The authors then quantified the expression levels of phalloidin and phosphorylated Tau in the mouse hippocampus
.
The results showed that lateral ventricle injection of BMSC-exos could reduce the accumulation of amyloid and the abnormal phosphorylation of Tau protein in the hippocampus of AD mice, and protected the structural integrity of neurons (Figure 6, Figure 7)
.
Figure 6 BMSC-exos inhibited the processing and accumulation of amyloid in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Figure 7 BMSC-exos reduced the phosphorylation level of Tau protein in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) The structural and functional integrity of neurons is the neurobiological basis of learning and memory, and neuronal damage is considered to be a downstream effect of amyloid and Tau and other AD pathogenesis [10]
.
Brain-derived neurotrophic factor (BDNF) can provide nutritional support for neurons, is one of the important regulators of synaptic plasticity, and can improve learning and memory impairment by reversing neuronal damage
.
The previous research results of Prof.
Jinfang Ge’s team showed that the changes in BDNF abundance in the hippocampus and prefrontal cortex and the related synaptic plasticity regulation-related proteins Synaptotagmin-1 (Syt-1), Synapsin-1 (Syn-1) and PSD95 expression decreased in the hippocampus and prefrontal cortex , and is closely related to learning and memory impairment and/or depression-like behavioral changes in various model animals such as stress, non-alcoholic fatty liver disease, subclinical hypothyroidism and AD[11-13]
.
The authors further detected the protein expression levels of BDNF, Syt-1 and Syn-1 in the mouse hippocampus
.
The results showed that the expression levels of Syt-1, Syn-1 and BDNF in the AD model group were significantly decreased, while BMSC-exos could increase the expression level of BDNF in the hippocampus of AD mice (Figure 8), indicating that BMSC-exos may It is involved in the regulation of hippocampal synaptic plasticity by up-regulating the expression of BDNF and promoting neuronal regeneration
.
Figure 8 BMSC-exos increased the expression level of BDNF in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Figure 9 Schematic diagram of the article: BMSC-exos rescues AD cells by promoting the expression of BDNF Cognitive decline in mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Conclusions and discussions, inspiration and prospects In summary, the team's research results suggest that administration of BMSC-exos to the lateral ventricle can improve the The mechanism of ureazotocin-induced AD-like neuropsychiatric behavioral abnormalities involves the regulation of hippocampal neuroinflammation and up-regulation of BDNF expression, thereby improving synaptic plasticity and reducing neuritic plaque accumulation, and reducing abnormal phosphorylation of Tau protein expression (Figure 9).
.
This study confirms the important role of BMSC-exos in anti-AD, and its core mechanism may be to improve BDNF-related neuropathology, providing a new approach and target for AD treatment research
.
Of course, there are still some unanswered scientific questions in this study, such as the underlying mechanism of how BMSC-exos regulates the changes of BDNF and its related signaling pathways, which needs to be further studied
.
Original link: https://jneuroinflammation.
biomedcentral.
com/articles/10.
1186/s12974-022-02393-2 Anhui Medical University School of Pharmacy Liu Sen (first from left) and Fan Min (second from left) are the first authors of this article, Anhui Professor Ge Jinfang (first from right), School of Pharmacy, Medical University, and Xia Qingrong, Director of Pharmacy Department of Affiliated Psychological Hospital (Hefei Fourth People's Hospital) (second from right) are the corresponding authors of this article
.
This work has been strongly supported by the School of Pharmacy of Anhui Medical University, the National Natural Science Foundation of China, the Anhui Provincial Key Laboratory of Major Autoimmune Diseases, and the Anhui Provincial Laboratory of Inflammatory and Immune Diseases
.
Ge Jinfang's research team (photo provided by: Ge Jinfang's research team) Selected from previous articles [1] Sci Transl Med︱GABAB receptor may save visual processing abnormalities in autistic patients [2] Sci Adv︱Xu Yong/Xu Pingping/ He Yanlin collaborated to discover the neural circuit mechanism of estrogen receptor neurons regulating body temperature and movement 【3】PNAS︱Han Chun’s group revealed a new mechanism of neuron degeneration caused by external phagocytosis 【4】Nat Neurosci︱VTA dopaminergic neurons are involved in coding Social prediction error and social reinforcement learning [5] Nature︱ New discovery! Inflammatory lymphocytes or new targets mediating CNS inflammation? 【6】Neurosci Bull︱Hu Bo’s research group reveals that the deep cerebellar nucleus neurons projecting to the ventromedial thalamus are specifically involved in the regulation of combined sensory-motor learning behavior 【7】Nat Neurosci︱Wu Longjun’s research group reveals the key pathological proteins of ALS The new ligand of TDP-43——TREM2【8】Cereb Cortex︱Luo Yuejia’s team revealed the cognitive control mechanism under the condition of uncertain expectation in anxious individuals 【9】PNAS︱Xiao Bo’s research group revealed a new mechanism for regulating the development of myelin in the central nervous system Mechanism【10】Science︱References of neuronal mechanisms controlling behavioral motivation (swipe up and down to view) 1.
R H.
Alzheimer's disease [J].
Nature, 2018,7715(559):S1.
2.
Pegtel DM, SJ G.
Exosomes [J].
Annu Rev Biochem, 2019(88):487-514.
3 .
Jin J, Shi Y, Gong J, et al.
Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte [J].
Stem Cell Research & Therapy, 2019,10(1).
4.
Yu B, Kim HW, Gong M, et al.
.
Exosomes are a class of extracellular vesicles with a diameter of about 30-200 nm, which carry important genetic information such as mRNA, miRNA, and proteins, and can mediate information transfer and communication between cells [2]
.
Exosomes derived from bone marrow mesenchymal stem cells (BMSC-exos) are extracellular vesicles that can perform the function of bone marrow mesenchymal stem cells.
Disease research has shown a certain therapeutic effect [3-6]
.
It has been reported that the neuroinflammation and neuronal apoptosis of primary neurons in AD transgenic mice were significantly inhibited after mesenchymal stem cell-derived exosomes [7]
.
In addition, studies have found that intranasal administration of mesenchymal stem cell-derived exosomes can reduce inflammation and prevent abnormal neurogenesis and memory dysfunction after status epilepticus [8]
.
However, the mechanisms underlying the effects of BMSC-exos on neuroinflammation and cognitive decline in AD model animals have not been elucidated
.
On February 7, 2022, the team of Prof.
Jinfang Ge from School of Pharmacy, Anhui Medical University, and Prof.
Qingrong Xia from the Affiliated Psychological Hospital published a paper entitled "Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like" in the Journal of Neuroinflammation.
The article "mice by improving BDNF-related neuropathology" describes how BMSC-exos alleviates the decline of learning and memory in AD model mice, and proves that BMSC-exos can reduce neuroinflammation in AD mice and reduce pale powder in the brain.
The accumulation of protein and decrease the phosphorylation level of tau protein and promote neurogenesis
.
In order to study the effect of BMSC-exos on the cognitive ability of AD mice, the authors cultured in vitro and purified bone marrow mesenchymal stem cells by flow sorting system, extracted their exosomes, and injected streptozotocin into the lateral ventricle.
Methods The AD mouse model was established, and the distribution of BMSC-exos labeled with PKH-26 fluorescent dye was observed after injecting into the lateral ventricle of the mouse (Fig.
1)
.
The results showed that BMSC-exos administered by intracerebroventricular injection were able to diffuse to the hippocampus along with the cerebral circulation (Fig.
2)
.
Figure 1 Experiment flow chart (STZ: streptozotocin, OFT: open field test, NOR: novel object recognition test, Y-maze: Y-maze test, TST: tail suspension test) (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Figure 2 BMSC-exos injection site and tracer (Source: Sen Liu et al.
, J Neuroinflammation.
2022) The authors observed the neuropsychiatric effects of BMSC-exos in AD mice through a classical neurobehavioral approach The results showed that compared with the model group, the AD model mice showed a significant increase in the novel object preference index in the novel object recognition experiment after the lateral ventricle injection of BMSC-exos, and the novel arm preference index in the Y-maze experiment also increased.
uptrend (Figure 3)
.
Figure 3 The effect of BMSC-exos on the behavioral performance of AD mice in NOR and Y-maze (Source: Sen Liu et al.
, J Neuroinflammation.
2022) The abnormal activation of glial cells is closely related to neuroinflammation, the authors further Immunofluorescence, Western blot and qPCR techniques were used to detect the expression levels of inflammatory factors and the activation of glial cells in the hippocampus of mice
.
The results showed that injection of BMSC-exos into the lateral ventricle could reduce the protein and mRNA expression levels of inflammatory factors IL-1β, IL-6 and TNF-α in the hippocampus of AD mice (Fig.
4), and inhibited the activation of microglia.
(Fig.
5), reduced neuroinflammation
.
Figure 4 BMSC-exos reduced the expression levels of IL-1β, IL-6 and TNF-α protein and mRNA in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Figure 5 BMSC-exos Inhibits the activation of microglia in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Microglia are involved in the clearance process of amyloid in the brain, and microglia in the inflammatory state Cells lose phagocytosis and promote neuroinflammation, which simultaneously promotes amyloid accumulation and indirectly leads to abnormal phosphorylation of Tau protein [9]
.
The authors then quantified the expression levels of phalloidin and phosphorylated Tau in the mouse hippocampus
.
The results showed that lateral ventricle injection of BMSC-exos could reduce the accumulation of amyloid and the abnormal phosphorylation of Tau protein in the hippocampus of AD mice, and protected the structural integrity of neurons (Figure 6, Figure 7)
.
Figure 6 BMSC-exos inhibited the processing and accumulation of amyloid in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Figure 7 BMSC-exos reduced the phosphorylation level of Tau protein in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) The structural and functional integrity of neurons is the neurobiological basis of learning and memory, and neuronal damage is considered to be a downstream effect of amyloid and Tau and other AD pathogenesis [10]
.
Brain-derived neurotrophic factor (BDNF) can provide nutritional support for neurons, is one of the important regulators of synaptic plasticity, and can improve learning and memory impairment by reversing neuronal damage
.
The previous research results of Prof.
Jinfang Ge’s team showed that the changes in BDNF abundance in the hippocampus and prefrontal cortex and the related synaptic plasticity regulation-related proteins Synaptotagmin-1 (Syt-1), Synapsin-1 (Syn-1) and PSD95 expression decreased in the hippocampus and prefrontal cortex , and is closely related to learning and memory impairment and/or depression-like behavioral changes in various model animals such as stress, non-alcoholic fatty liver disease, subclinical hypothyroidism and AD[11-13]
.
The authors further detected the protein expression levels of BDNF, Syt-1 and Syn-1 in the mouse hippocampus
.
The results showed that the expression levels of Syt-1, Syn-1 and BDNF in the AD model group were significantly decreased, while BMSC-exos could increase the expression level of BDNF in the hippocampus of AD mice (Figure 8), indicating that BMSC-exos may It is involved in the regulation of hippocampal synaptic plasticity by up-regulating the expression of BDNF and promoting neuronal regeneration
.
Figure 8 BMSC-exos increased the expression level of BDNF in the hippocampus of AD mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Figure 9 Schematic diagram of the article: BMSC-exos rescues AD cells by promoting the expression of BDNF Cognitive decline in mice (Source: Sen Liu et al.
, J Neuroinflammation.
2022) Conclusions and discussions, inspiration and prospects In summary, the team's research results suggest that administration of BMSC-exos to the lateral ventricle can improve the The mechanism of ureazotocin-induced AD-like neuropsychiatric behavioral abnormalities involves the regulation of hippocampal neuroinflammation and up-regulation of BDNF expression, thereby improving synaptic plasticity and reducing neuritic plaque accumulation, and reducing abnormal phosphorylation of Tau protein expression (Figure 9).
.
This study confirms the important role of BMSC-exos in anti-AD, and its core mechanism may be to improve BDNF-related neuropathology, providing a new approach and target for AD treatment research
.
Of course, there are still some unanswered scientific questions in this study, such as the underlying mechanism of how BMSC-exos regulates the changes of BDNF and its related signaling pathways, which needs to be further studied
.
Original link: https://jneuroinflammation.
biomedcentral.
com/articles/10.
1186/s12974-022-02393-2 Anhui Medical University School of Pharmacy Liu Sen (first from left) and Fan Min (second from left) are the first authors of this article, Anhui Professor Ge Jinfang (first from right), School of Pharmacy, Medical University, and Xia Qingrong, Director of Pharmacy Department of Affiliated Psychological Hospital (Hefei Fourth People's Hospital) (second from right) are the corresponding authors of this article
.
This work has been strongly supported by the School of Pharmacy of Anhui Medical University, the National Natural Science Foundation of China, the Anhui Provincial Key Laboratory of Major Autoimmune Diseases, and the Anhui Provincial Laboratory of Inflammatory and Immune Diseases
.
Ge Jinfang's research team (photo provided by: Ge Jinfang's research team) Selected from previous articles [1] Sci Transl Med︱GABAB receptor may save visual processing abnormalities in autistic patients [2] Sci Adv︱Xu Yong/Xu Pingping/ He Yanlin collaborated to discover the neural circuit mechanism of estrogen receptor neurons regulating body temperature and movement 【3】PNAS︱Han Chun’s group revealed a new mechanism of neuron degeneration caused by external phagocytosis 【4】Nat Neurosci︱VTA dopaminergic neurons are involved in coding Social prediction error and social reinforcement learning [5] Nature︱ New discovery! Inflammatory lymphocytes or new targets mediating CNS inflammation? 【6】Neurosci Bull︱Hu Bo’s research group reveals that the deep cerebellar nucleus neurons projecting to the ventromedial thalamus are specifically involved in the regulation of combined sensory-motor learning behavior 【7】Nat Neurosci︱Wu Longjun’s research group reveals the key pathological proteins of ALS The new ligand of TDP-43——TREM2【8】Cereb Cortex︱Luo Yuejia’s team revealed the cognitive control mechanism under the condition of uncertain expectation in anxious individuals 【9】PNAS︱Xiao Bo’s research group revealed a new mechanism for regulating the development of myelin in the central nervous system Mechanism【10】Science︱References of neuronal mechanisms controlling behavioral motivation (swipe up and down to view) 1.
R H.
Alzheimer's disease [J].
Nature, 2018,7715(559):S1.
2.
Pegtel DM, SJ G.
Exosomes [J].
Annu Rev Biochem, 2019(88):487-514.
3 .
Jin J, Shi Y, Gong J, et al.
Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte [J].
Stem Cell Research & Therapy, 2019,10(1).
4.
Yu B, Kim HW, Gong M, et al.
