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Written | Qi neural stem cells residing in the hippocampal neurogenesis microenvironment maintain lifelong neurogenesis in the adult brain
.
Adult hippocampal neurogenesis (AHN) is functionally related to memory and cognitive plasticity in humans and rodents
.
In Alzheimer's disease (AD), the process of generating new neurons in the hippocampal neurogenesis microenvironment is hindered, but the mechanism is unclear
.
When AHN is regarded as a therapeutic target for neurodegenerative diseases (such as AD), a deeper understanding of the molecular mechanisms involved in AHN becomes particularly important
.
Previous studies have demonstrated that the absence of miR-132 in the adult dentate gyrus can cause the maturation of new neurons and neurites, spine formation and significant changes in synaptic activity, thereby impairing their functional integration into the adult hippocampal circuit [1]
.
Cross-analysis of hippocampal transcriptome profiles in miR-132 overexpression and miR-132 conditional gene knockout mice revealed its powerful influence on genes involved in neurogenesis and cell proliferation [2]
.
Interestingly, miR-132 is strongly down-regulated in the hippocampus of human AD patients.
In addition, the overexpression of miR-132 in primary neurons or mouse brain inhibits the pathological features of AD, such as amyloid plaques and tau hyperphosphate.
And deposition and neuron death [3, 4]
.
However, the role of miR-132 in the AHN of AD patients is still elusive
.
On May 24, 2021, the Evgenia Salta team from the Netherlands Institute of Neuroscience and the Bart De Strooper team from the VIB Brain and Disease Research Center in Belgium published an article entitled Restoring miR-132 expression rescues adult in Cell Stem Cell.
Hippocampal neurogenesis and memory deficits in Alzheimer's disease article.
This study reported that miR-132 regulation is an integral part of AHN, and supplementary miR-132 plays different roles in the adult hippocampal neurogenesis microenvironment, thereby in two Recovery of AHN and memory deficits in different AD mouse models
.
This finding confirms the importance of AHN in AD mouse models and reveals the potential therapeutic potential of targeting miR-132 in neurodegenerative diseases
.
Based on previous research, the author wanted to know whether the lack of miR-132 in AD is related to the function of the AHN microenvironment
.
In order to rule out possible gene shifts, the authors used two AD mouse models to complete the follow-up study, one that overexpresses human amyloid precursor protein (APP) and presenilin 1 (PS1) (APP / PS1) mutations In the form, another knock-in mutation of the humanized App gene (AppNL-GF)
.
The authors detected that compared with wild-type mice, miR-132 was significantly down-regulated in the dentate gyrus of the two AD mice, and the degree of impairment of neuron progenitor cell proliferation was parallel to the changes in miR-132 levels, suggesting that miR-132 and miR-132 There may be a correlation between AHN
.
Next, the author uses Nestin: GFP reporter gene lineage combined with other markers to label neural stem cells (NSCs) and neuron precursor cells in the dentate gyrus, and uses fluorescence in situ hybridization and FACS to confirm adulthood NSCs and progenitor cells recruit miR-132 as part of their response to exercise or aging-related stimuli.
However, miR-132 is not recruited when AHN is exposed to Aβ
.
Interestingly, the knockdown of miR-132 inhibits the increase of the key neurotrophic factor Bdnf, which has been proved to be an essential substance for the health and cognitive recovery of the adult hippocampal neurogenesis microenvironment [5]
.
It is worth noting that the overexpression of miR132 in human neuron precursors in vitro and adult mouse NSC and progenitor cells induces neuronal differentiation and maturation in a cell-autonomous manner, and neuronal primary human embryonic stem cells induce neuronal precursors Later, the level of miR-132 was significantly increased by 20 times, and it was further increased by more than 300 times during the process of neuron maturation.
These data further confirmed the correlation between miR-132 regulation and human neurogenesis
.
Then think in reverse, if increasing the level of miR-132 can improve the AHN deficiency observed in the two mouse models? The authors found that overexpression of miR-132 can significantly inhibit the characteristics of early stem cells in the cell pool and induce transcriptome changes related to increased proliferation and differentiation rates
.
In addition to changes at the molecular level, does miR-132's regulation of AHN affect related memory functions? To this end, the authors evaluated the effects of overexpression of miR-132 in AppNL-GF mice in the passive avoidance test and the pattern separation (based on differential fear conditions) test
.
The authors found that restoring the expression of miR-132 can rescue the hippocampal-dependent functional characteristics related to situational fear regulation and avoidance tasks, and these functions are related to the lack of AHN in the AD mouse model
.
Interestingly, the overexpression of miR-132 in wild-type mice leads to a decrease in performance in AHN-specific pattern separation tasks, which indicates that the expression of miR-132 should be kept within a certain range to ensure proper learning and memory functions This result further confirms the results of a previous study that "superphysiological" (> 3 times) miR-132 levels can inhibit hippocampal-dependent memory in wild-type mice
.
Therefore, these results suggest that further work is needed to assess the therapeutic window of miR-132 overexpression in AD brain
.
Overall, this study supports a model in which miR-132 is an effective regulator of adult neurogenesis in mice and humans, and the pathological changes of AD can lead to miR-132 deficiency and damage AHN.
On the contrary, in adult NSCs Overexpression of a certain range of miR-132 can rescue the neurogenesis and memory deficits in AD mouse models
.
Recently, the use of RNA-based small-scale therapy in spinal muscular atrophy to treat neurodegenerative diseases has achieved breakthrough progress [6], so this research may be able to pave the way for miR-132-based treatment of AD, of course In the future, there are two issues that need to be addressed: first, the appropriate dose will be crucial; in addition, solving the molecular and cellular mechanisms that miR-132 depends on the regulation of neurogenesis can also enable new strategies to be proposed.
Reliability and persuasiveness
.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
05.
001 Plate maker: Eleven References 1.
Luikart, BW, Bensen, AL, Washburn, EK, Perederiy, JV, Su, KG, Li , Y.
, Kernie, SG, Parada, LF, and Westbrook, GL (2011).
miR-132 mediates the integration of newborn neurons into the adult dentate gyrus.
PLoS ONE 6, e19077.
2.
Hansen, KF, Sakamoto, K .
, Aten, S.
, Snider, KH, Loeser, J.
, Hesse, AM, Page, CE, Pelz, C.
, Arthur, JSC, Impey, S.
, and Obrietan, K.
(2016).
Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome.
Learn.
Mem.
23, 61–71.
3.
He ´ bert, SS, Wang, WX, Zhu, Q.
, and Nelson, PT (2013).
A study of small RNAs from cerebral neocortex of pathology-verified Alzheimer's disease, dementia with lewy bodies, hippocampal sclerosis, frontotemporal lobar dementia, and non-demented human controls.
J.
Alzheimers Dis.
35,335–348.
4.
El Fatimy, R.
, Li, S.
, Chen, Z.
, Mushannen, T.
, Gongala, S.
, Wei, Z.
, Balu, DT, Rabinovsky, R.
, Cantlon, A.
, Elkhal , A.
, et al.
(2018).
MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways.
Acta Neuropathol.
136, 537–555.
5.
Choi, SH, Bylykbashi, E.
, Chatila, ZK, Lee, SW, Pulli , B.
, Clemenson, GD, Kim, E.
, Rompala, A.
, Oram, MK, Asselin, C.
, et al.
(2018).
Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model.
Science 361, eaan8821.
6.
Finkel, RS, Chiriboga, CA, Vajsar, J.
, Day, JW, Montes, J.
, De Vivo, DC, Yamashita, M.
, Rigo, F.
, Hung, G.
, Schneider , E.
, et al.
(2016).
Treatment of infantile onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study.
Lancet 388, 3017–3026.
Reprinting instructions [Original articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt. .
BioArt reserves all statutory rights and offenders must be investigated
.
.
Adult hippocampal neurogenesis (AHN) is functionally related to memory and cognitive plasticity in humans and rodents
.
In Alzheimer's disease (AD), the process of generating new neurons in the hippocampal neurogenesis microenvironment is hindered, but the mechanism is unclear
.
When AHN is regarded as a therapeutic target for neurodegenerative diseases (such as AD), a deeper understanding of the molecular mechanisms involved in AHN becomes particularly important
.
Previous studies have demonstrated that the absence of miR-132 in the adult dentate gyrus can cause the maturation of new neurons and neurites, spine formation and significant changes in synaptic activity, thereby impairing their functional integration into the adult hippocampal circuit [1]
.
Cross-analysis of hippocampal transcriptome profiles in miR-132 overexpression and miR-132 conditional gene knockout mice revealed its powerful influence on genes involved in neurogenesis and cell proliferation [2]
.
Interestingly, miR-132 is strongly down-regulated in the hippocampus of human AD patients.
In addition, the overexpression of miR-132 in primary neurons or mouse brain inhibits the pathological features of AD, such as amyloid plaques and tau hyperphosphate.
And deposition and neuron death [3, 4]
.
However, the role of miR-132 in the AHN of AD patients is still elusive
.
On May 24, 2021, the Evgenia Salta team from the Netherlands Institute of Neuroscience and the Bart De Strooper team from the VIB Brain and Disease Research Center in Belgium published an article entitled Restoring miR-132 expression rescues adult in Cell Stem Cell.
Hippocampal neurogenesis and memory deficits in Alzheimer's disease article.
This study reported that miR-132 regulation is an integral part of AHN, and supplementary miR-132 plays different roles in the adult hippocampal neurogenesis microenvironment, thereby in two Recovery of AHN and memory deficits in different AD mouse models
.
This finding confirms the importance of AHN in AD mouse models and reveals the potential therapeutic potential of targeting miR-132 in neurodegenerative diseases
.
Based on previous research, the author wanted to know whether the lack of miR-132 in AD is related to the function of the AHN microenvironment
.
In order to rule out possible gene shifts, the authors used two AD mouse models to complete the follow-up study, one that overexpresses human amyloid precursor protein (APP) and presenilin 1 (PS1) (APP / PS1) mutations In the form, another knock-in mutation of the humanized App gene (AppNL-GF)
.
The authors detected that compared with wild-type mice, miR-132 was significantly down-regulated in the dentate gyrus of the two AD mice, and the degree of impairment of neuron progenitor cell proliferation was parallel to the changes in miR-132 levels, suggesting that miR-132 and miR-132 There may be a correlation between AHN
.
Next, the author uses Nestin: GFP reporter gene lineage combined with other markers to label neural stem cells (NSCs) and neuron precursor cells in the dentate gyrus, and uses fluorescence in situ hybridization and FACS to confirm adulthood NSCs and progenitor cells recruit miR-132 as part of their response to exercise or aging-related stimuli.
However, miR-132 is not recruited when AHN is exposed to Aβ
.
Interestingly, the knockdown of miR-132 inhibits the increase of the key neurotrophic factor Bdnf, which has been proved to be an essential substance for the health and cognitive recovery of the adult hippocampal neurogenesis microenvironment [5]
.
It is worth noting that the overexpression of miR132 in human neuron precursors in vitro and adult mouse NSC and progenitor cells induces neuronal differentiation and maturation in a cell-autonomous manner, and neuronal primary human embryonic stem cells induce neuronal precursors Later, the level of miR-132 was significantly increased by 20 times, and it was further increased by more than 300 times during the process of neuron maturation.
These data further confirmed the correlation between miR-132 regulation and human neurogenesis
.
Then think in reverse, if increasing the level of miR-132 can improve the AHN deficiency observed in the two mouse models? The authors found that overexpression of miR-132 can significantly inhibit the characteristics of early stem cells in the cell pool and induce transcriptome changes related to increased proliferation and differentiation rates
.
In addition to changes at the molecular level, does miR-132's regulation of AHN affect related memory functions? To this end, the authors evaluated the effects of overexpression of miR-132 in AppNL-GF mice in the passive avoidance test and the pattern separation (based on differential fear conditions) test
.
The authors found that restoring the expression of miR-132 can rescue the hippocampal-dependent functional characteristics related to situational fear regulation and avoidance tasks, and these functions are related to the lack of AHN in the AD mouse model
.
Interestingly, the overexpression of miR-132 in wild-type mice leads to a decrease in performance in AHN-specific pattern separation tasks, which indicates that the expression of miR-132 should be kept within a certain range to ensure proper learning and memory functions This result further confirms the results of a previous study that "superphysiological" (> 3 times) miR-132 levels can inhibit hippocampal-dependent memory in wild-type mice
.
Therefore, these results suggest that further work is needed to assess the therapeutic window of miR-132 overexpression in AD brain
.
Overall, this study supports a model in which miR-132 is an effective regulator of adult neurogenesis in mice and humans, and the pathological changes of AD can lead to miR-132 deficiency and damage AHN.
On the contrary, in adult NSCs Overexpression of a certain range of miR-132 can rescue the neurogenesis and memory deficits in AD mouse models
.
Recently, the use of RNA-based small-scale therapy in spinal muscular atrophy to treat neurodegenerative diseases has achieved breakthrough progress [6], so this research may be able to pave the way for miR-132-based treatment of AD, of course In the future, there are two issues that need to be addressed: first, the appropriate dose will be crucial; in addition, solving the molecular and cellular mechanisms that miR-132 depends on the regulation of neurogenesis can also enable new strategies to be proposed.
Reliability and persuasiveness
.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
05.
001 Plate maker: Eleven References 1.
Luikart, BW, Bensen, AL, Washburn, EK, Perederiy, JV, Su, KG, Li , Y.
, Kernie, SG, Parada, LF, and Westbrook, GL (2011).
miR-132 mediates the integration of newborn neurons into the adult dentate gyrus.
PLoS ONE 6, e19077.
2.
Hansen, KF, Sakamoto, K .
, Aten, S.
, Snider, KH, Loeser, J.
, Hesse, AM, Page, CE, Pelz, C.
, Arthur, JSC, Impey, S.
, and Obrietan, K.
(2016).
Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome.
Learn.
Mem.
23, 61–71.
3.
He ´ bert, SS, Wang, WX, Zhu, Q.
, and Nelson, PT (2013).
A study of small RNAs from cerebral neocortex of pathology-verified Alzheimer's disease, dementia with lewy bodies, hippocampal sclerosis, frontotemporal lobar dementia, and non-demented human controls.
J.
Alzheimers Dis.
35,335–348.
4.
El Fatimy, R.
, Li, S.
, Chen, Z.
, Mushannen, T.
, Gongala, S.
, Wei, Z.
, Balu, DT, Rabinovsky, R.
, Cantlon, A.
, Elkhal , A.
, et al.
(2018).
MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways.
Acta Neuropathol.
136, 537–555.
5.
Choi, SH, Bylykbashi, E.
, Chatila, ZK, Lee, SW, Pulli , B.
, Clemenson, GD, Kim, E.
, Rompala, A.
, Oram, MK, Asselin, C.
, et al.
(2018).
Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model.
Science 361, eaan8821.
6.
Finkel, RS, Chiriboga, CA, Vajsar, J.
, Day, JW, Montes, J.
, De Vivo, DC, Yamashita, M.
, Rigo, F.
, Hung, G.
, Schneider , E.
, et al.
(2016).
Treatment of infantile onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study.
Lancet 388, 3017–3026.
Reprinting instructions [Original articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt. .
BioArt reserves all statutory rights and offenders must be investigated
.
