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Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, with a typical feature of progressive cognitive dysfunction.
Synapse loss and synaptic dysfunction have occurred in the early stages of AD patients, and synapses are the most critical unit structure for the formation of learning and memory.
MicroRNAs (miRNAs) are a type of non-coding RNA with a length of about 22bp.
Studies have shown that miRNAs can precisely regulate the local translation of synapse-related proteins.
In the brain tissue or serum of patients with Alzheimer's disease, some miRNAs are thought to be involved in the formation of senile plaques and neurofibrillary tangles.
On March 26, 2021, the research team of Professor Zhu Lingqiang and Professor Lu Youming of the Department of Pathophysiology, Department of Pathophysiology, Huazhong University of Science and Technology of Huazhong University of Science and Technology published an article in the journal Nature Communications revealing that synaptic function-related miR-135a-5p regulates AD Synaptic dysfunction.
Changes of miRNAs in the hippocampus of AD model mice.
Researchers screened the miRNAs related to synaptic activity in the hippocampus of AD model mice and found that miR-136-3p, miR- in 12-month-old AD model mice 19a-3p, miR-125b-5p, and miR-26a-5p are up-regulated, and only miR-135a-5p is down-regulated.
In terms of time dimension, this down-regulation of miR-135a-5p has existed since 6 months of age, but the down-regulation of miR-135a-5p was more pronounced in 9-month-old model mice.
In addition, miR-135a-5p was down-regulated in hippocampal tissue samples of AD patients, indicating that this type of RNA is involved in the early onset of AD disease.
AAV viral vector tool inhibits the activity of miR-135a-5p and causes cognitive impairment in normal mice.
In situ hybridization experiments have found that miR-135a-5p is expressed in the hippocampal excitatory neurons of AD model mice.
The expression of miR-135a-5p is reduced on the inhibitory neurons.
The expression has not diminished.
The researchers used the AAV virus vector to inhibit miR-135a-5p, and found that after the hippocampus of wild-type mice were injected with the virus, the spatial memory ability was impaired, which was manifested in the prolonged latency to the platform for the first time in the water maze experiment, the Barnes maze (Barnes maze) In the experiment, the latency to reach the target box is also extended.
Synaptic plasticity is the foundation of learning and memory.
Researchers also found that after infection with the above-mentioned miR-135a-5p-inhibiting virus, the synaptic transmission function in the hippocampus was abnormal.
In addition, in terms of morphological structure, the dendritic spine density of hippocampal neurons is reduced after miR-135a-5p is inhibited, especially the mushroom-type dendritic spine that is closely related to memory.
The dendritic complexity of neurons is also reduced, which to a certain extent reflects that the complexity of neural connections is also decreasing.
Generally speaking, miRNAs regulate gene expression by inhibiting translation or promoting the degradation of target mRNAs.
In order to further find the downstream targets of miRNAs causing abnormal synaptic function, they compared multiple databases and found that Rock1, Rock2, Cacna1d and Pik3r2 are potential candidate molecules.
On the other hand, among the four candidate targets mentioned above in AD model mice, only Rock2 changed significantly and was up-regulated.
In vitro cell experiments show that after promoting or inhibiting the expression of miR-135a-5p, the level of Rock2 will be down-regulated or up-regulated accordingly, showing a clear trend of you ascending and me descending, and you descending as me ascending, indicating that miR-135a-5p can be directly transcribed After regulating Rock2.
By injecting miR-135a-5p mimics or LV virus that silences Rock2 expression into the hippocampus of 9-month-old AD model mice, the dendritic spine density of neurons returned to normal levels, and the synaptic transmission function also returned to normal.
Synaptic function has been restored to normal levels. Correspondingly, the learning and memory impairment of AD model mice has also been significantly improved.
This indicates that the miR-135a-5p/Rock2 signaling pathway is involved in the early synaptic pathology of AD.
In summary, this article reveals that miR-135a-5p/Rock2 signals mediate learning and memory impairment by regulating synaptic-related functions in the early synaptic pathology of AD.
[References] 1.
https://doi.
org/10.
1038/s41467-021-22196-y The pictures in the article are all from the references
Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, with a typical feature of progressive cognitive dysfunction.
Synapse loss and synaptic dysfunction have occurred in the early stages of AD patients, and synapses are the most critical unit structure for the formation of learning and memory.
MicroRNAs (miRNAs) are a type of non-coding RNA with a length of about 22bp.
Studies have shown that miRNAs can precisely regulate the local translation of synapse-related proteins.
In the brain tissue or serum of patients with Alzheimer's disease, some miRNAs are thought to be involved in the formation of senile plaques and neurofibrillary tangles.
On March 26, 2021, the research team of Professor Zhu Lingqiang and Professor Lu Youming of the Department of Pathophysiology, Department of Pathophysiology, Huazhong University of Science and Technology of Huazhong University of Science and Technology published an article in the journal Nature Communications revealing that synaptic function-related miR-135a-5p regulates AD Synaptic dysfunction.
Changes of miRNAs in the hippocampus of AD model mice.
Researchers screened the miRNAs related to synaptic activity in the hippocampus of AD model mice and found that miR-136-3p, miR- in 12-month-old AD model mice 19a-3p, miR-125b-5p, and miR-26a-5p are up-regulated, and only miR-135a-5p is down-regulated.
In terms of time dimension, this down-regulation of miR-135a-5p has existed since 6 months of age, but the down-regulation of miR-135a-5p was more pronounced in 9-month-old model mice.
In addition, miR-135a-5p was down-regulated in hippocampal tissue samples of AD patients, indicating that this type of RNA is involved in the early onset of AD disease.
AAV viral vector tool inhibits the activity of miR-135a-5p and causes cognitive impairment in normal mice.
In situ hybridization experiments have found that miR-135a-5p is expressed in the hippocampal excitatory neurons of AD model mice.
The expression of miR-135a-5p is reduced on the inhibitory neurons.
The expression has not diminished.
The researchers used the AAV virus vector to inhibit miR-135a-5p, and found that after the hippocampus of wild-type mice were injected with the virus, the spatial memory ability was impaired, which was manifested in the prolonged latency to the platform for the first time in the water maze experiment, the Barnes maze (Barnes maze) In the experiment, the latency to reach the target box is also extended.
Synaptic plasticity is the foundation of learning and memory.
Researchers also found that after infection with the above-mentioned miR-135a-5p-inhibiting virus, the synaptic transmission function in the hippocampus was abnormal.
In addition, in terms of morphological structure, the dendritic spine density of hippocampal neurons is reduced after miR-135a-5p is inhibited, especially the mushroom-type dendritic spine that is closely related to memory.
The dendritic complexity of neurons is also reduced, which to a certain extent reflects that the complexity of neural connections is also decreasing.
Generally speaking, miRNAs regulate gene expression by inhibiting translation or promoting the degradation of target mRNAs.
In order to further find the downstream targets of miRNAs causing abnormal synaptic function, they compared multiple databases and found that Rock1, Rock2, Cacna1d and Pik3r2 are potential candidate molecules.
On the other hand, among the four candidate targets mentioned above in AD model mice, only Rock2 changed significantly and was up-regulated.
In vitro cell experiments show that after promoting or inhibiting the expression of miR-135a-5p, the level of Rock2 will be down-regulated or up-regulated accordingly, showing a clear trend of you ascending and me descending, and you descending as me ascending, indicating that miR-135a-5p can be directly transcribed After regulating Rock2.
By injecting miR-135a-5p mimics or LV virus that silences Rock2 expression into the hippocampus of 9-month-old AD model mice, the dendritic spine density of neurons returned to normal levels, and the synaptic transmission function also returned to normal.
Synaptic function has been restored to normal levels. Correspondingly, the learning and memory impairment of AD model mice has also been significantly improved.
This indicates that the miR-135a-5p/Rock2 signaling pathway is involved in the early synaptic pathology of AD.
In summary, this article reveals that miR-135a-5p/Rock2 signals mediate learning and memory impairment by regulating synaptic-related functions in the early synaptic pathology of AD.
[References] 1.
https://doi.
org/10.
1038/s41467-021-22196-y The pictures in the article are all from the references
