miR-351-5p/Miro2 axis contributes to hippocampal neural progenitor cell death via unbalanced mitochondrial fission

Abstract

Adult hippocampal neurogenesis supports the structural and functional plasticity of the brain, while its decline is associated with neurodegeneration common in Alzheimer’s disease (AD). Although the dysregulation of certain microRNAs (miRNAs) in AD have been observed, the effects of miRNAs on hippocampal neurogenesis are largely unknown.In this study, we demonstrated miR-351-5p as a causative factor in hippocampal neural progenitor cell death through modulation of the mitochondrial guanosine triphosphatase (GTPase), Miro2. Downregulation of Miro2 by siMiro2 induced cell death, similar to miR-351-5p, whereas ectopic Miro2 expression using an adenovirus abolished these effects. Excessively fragmented mitochondria and dysfunctional mitochondria were indexed by decreased mitochondrial potential, and increased reactive oxygen species were identified in miR-351-5p-induced cell death. Moreover, subsequent induction of mitophagy via Pink1 and Parkin was observed in the presence of miR-351-5p and siMiro2. The suppression of mitochondrial fission by Mdivi-1 completely inhibited cell death by miR-351-5p. miR-351-5p expression increased whereas the level of Miro2 decreased in the hippocampus of AD model mice, emulating expression in AD patients. Collectively, the data indicate the mitochondrial fission and accompanying mitophagy by miR-351-5p/Miro2 axis as critical in hippocampal neural progenitor cell death, and a potential therapeutic target in AD. Adult hippocampal neurogenesis supports the structural and functional plasticity of the brain, while its decline is associated with neurodegeneration common in Alzheimer’s disease (AD). Although the dysregulation of certain microRNAs (miRNAs) in AD have been observed, the effects of miRNAs on hippocampal neurogenesis are largely unknown. In this study, we demonstrated miR-351-5p as a causative factor in hippocampal neural progenitor cell death through modulation of the mitochondrial guanosine triphosphatase (GTPase), Miro2. Downregulation of Miro2 by siMiro2 induced cell death, similar to miR-351-5p, whereas ectopic Miro2 expression using an adenovirus abolished these effects. Excessively fragmented mitochondria and dysfunctional mitochondria were indexed by decreased mitochondrial potential, and increased reactive oxygen species were identified in miR-351-5p-induced cell death. Moreover, subsequent induction of mitophagy via Pink1 and Parkin was observed in the presence of miR-351-5p and siMiro2. The suppression of mitochondrial fission by Mdivi-1 completely inhibited cell death by miR-351-5p. miR-351-5p expression increased whereas the level of Miro2 decreased in the hippocampus of AD model mice, emulating expression in AD patients. Collectively, the data indicate the mitochondrial fission and accompanying mitophagy by miR-351-5p/Miro2 axis as critical in hippocampal neural progenitor cell death, and a potential therapeutic target in AD. IntroductionAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the loss of neurons and synapses, synaptic dysfunction, mitochondrial dysfunction, and inflammatory responses, along with extracellular amyloid plaques and intracellular neurofibrillary tangles.1Scheltens P. Blennow K. Breteler M.M. de Strooper B. Frisoni G.B. Salloway S. Van der Flier W.M. Alzheimer’s disease.Lancet. 2016; 388: 505-517Abstract Full Text Full Text PDF PubMed Scopus (1801) Google Scholar Various factors are involved in the reduction of cognitive resilience linked with chronic neurodegenerative disease, including AD. New neurons are generated from multipotent neural progenitor cells in the dentate gyrus (DG) of the hippocampus throughout life, although neuroplasticity may be somewhat affected with age.2Boldrini M. Fulmore C.A. Tartt A.N. Simeon L.R. Pavlova I. Poposka V. Rosoklija G.B. Stankov A. Arango V. Dwork A.J. et al.Human hippocampal neurogenesis persists throughout aging.Cell Stem Cell. 2018; 22: 589-599.e5Abstract Full Text Full Text PDF PubMed Scopus (683) Google Scholar The hippocampus is one of the most affected areas in AD. Decreased neurogenesis in the hippocampus is a critical factor contributing to neurodegenerative defects owing to a declined neural progenitor pool caused by excessive cell death in the hippocampal neurogenic niche.3Toda T. Parylak S.L. Linker S.B. Gage F.H. The role of adult hippocampal neurogenesis in brain health and disease.Mol. Psychiatry. 2019; 24: 67-87Crossref PubMed Scopus (246) Google Scholar Recent reports strongly suggest that impaired adult neurogenesis in the hippocampus is a potentially relevant mechanism underlying memory deficits in AD.4Moreno-Jiménez E.P. Flor-García M. Terreros-Roncal J. Rábano A. Cafini F. Pallas-Bazarra N. Ávila J. Llorens-Martín M. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease.Nat. Med. 2019; 25: 554-560Crossref PubMed Scopus (671) Google ScholarAdult hippocampal neural progenitor (HCN) cells have previously been isolated from the adult rat brain by Gage group5Ray J. Peterson D.A. Schinstine M. Gage F.H. Proliferation, differentiation, and long-term culture of primary hippocampal neurons.Proc. Natl. Acad. Sci. USA. 1993; 90: 3602-3606Crossref PubMed Scopus (403) Google Scholar and differentiated into neurons, astrocytes, or oligodendrocytes in vitro and in vivo. HCN cells have also been proven to functionally integrate into existing neuronal networks in vivo.6Reynolds B.A. Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.Science. 1992; 255: 1707-1710Crossref PubMed Scopus (4510) Google Scholar Their proliferation and differentiation can be regulated by various exogenous and endogenous factors.7Palmer T.D. Markakis E.A. Willhoite A.R. Safar F. Gage F.H. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS.J. Neurosci. 1999; 19: 8487-8497Crossref PubMed Google Scholar Among these, insulin is known as a critical regulator of HCN cell death. Previously we reported that HCN cells undergo cell death with excessive in the of et death of adult hippocampal neural stem cells insulin PubMed Scopus Google Scholar to a of in neural stem cells the death of hippocampal neural stem cells induced by chronic S. S. et death of neural stem cells chronic decline of adult hippocampal neurogenesis and cognitive PubMed Scopus Google Scholar data indicate that HCN cells can be a model the of adult neurogenesis and cell death B. M. K. M. M. et and neurodegeneration in Neurosci. 22: PubMed Google Scholar the that HCN cell death largely in mitochondrial caused by the of and are known to be associated with K. B.A. B. S. M.M. et and and cognitive deficits in of Alzheimer’s disease.Nat. Neurosci. 2019; 22: PubMed Scopus Google Scholar a role in cells and of cell death, including and mitochondrial is regulated by mitochondrial as mitochondrial and of mitochondrial 2019; PubMed Scopus Google Scholar fission and mitochondrial and mitochondrial fission is by the guanosine triphosphatase whereas and and and N. K. and in mitochondrial via Sci. PubMed Scopus Google N. P. J. et a mitochondrial is in PubMed Scopus Google Scholar and mitochondrial in to Recent a functional mitochondrial and mitochondrial fission mitochondria to through S. P. and in mitochondrial 2018; Full Text Full Text PDF PubMed Scopus Google K. N. of mitophagy in and 2018; PubMed Scopus Google we and reported that microRNAs including miR-351-5p, expression death of HCN S. expression of adult hippocampal neural stem cells cell death an cell 2019; PubMed Scopus Google Scholar identified that increased of miR-351-5p HCN cell death the underlying HCN cell death miRNAs are endogenous in expression the level through to the of a with a miRNAs are involved in diverse including cell differentiation, and cell death. the nervous of is that miRNAs as critical of neuronal differentiation, and synaptic plasticity in the miRNAs in and of the nervous PubMed Scopus Google to the of miR-351-5p to HCN cell death, we that Miro2 be the target of miR-351-5p. is an on the mitochondrial in and Miro2. have that are involved in mitochondrial including and M. S. A. P. of mitochondrial by the Natl. Acad. Sci. USA. PubMed Scopus Google Scholar are involved in mitophagy through and by T. J. Parkin and mitochondrial Natl. Acad. Sci. USA. 2016; PubMed Scopus Google Scholar is also known that of in disease are to mitochondrial J. F. A. A. et in with and mitochondrial in 2019; PubMed Scopus Google the study, we on miR-351-5p and its target Miro2 to in HCN cell death to the of mitochondrial and the of these to Miro2 is the target of previously reported that miR-351-5p is cell death along with induction in HCN S. expression of adult hippocampal neural stem cells cell death an cell 2019; PubMed Scopus Google Scholar of target including and we mitochondrial Miro2 as a potential target of miR-351-5p. The of Miro2 one to the of miR-351-5p the of or Miro2 with the miR-351-5p target were was through a with miR-351-5p in cells with the miR-351-5p inhibited by miR-351-5p the of Miro2 and by and and indicate that miR-351-5p Miro2 in HCN and its target Miro2 cell death in HCN the of cell of miR-351-5p on HCN cells with miR-351-5p and were with miR-351-5p and the of cell death was with and miR-351-5p sharply induced HCN cell death, was inhibited through with in a the of of Miro2 by miR-351-5p, HCN cells were with siMiro2 and with the siMiro2 increased cell death by in HCN cells and The data indicate that miR-351-5p and its target Miro2 potentially HCN cell of miR-351-5p or suppression of its target Miro2 induced cell death in HCN and HCN cells were with miR-351-5p, or with and cell death was by inhibited miR-351-5p-induced cell death in a and HCN cells were with or siMiro2. cell death was using the of Miro2 induced cell death in HCN in the the of Miro2 by miR-351-5p in HCN and HCN cells an in of as identified and using data The of was in the miR-351-5p in the siMiro2 and in the The and of with and of as are is associated with and an that is the miR-351-5p increased and with miR-351-5p and completely and The level of was regulated by miR-351-5p and a and of Miro2 by miR-351-5p in HCN was by the cell miR-351-5p and siMiro2 increased the of to the with miR-351-5p or cells were with or were and by using and was as a of the The of was using was using with miR-351-5p or cells were observed a was of from cells cells miR-351-5p, and cells from and were with and miR-351-5p or cell death was using the death induced by siMiro2 and miR-351-5p was in the presence of and in the the we a J. F. A. A. et in with and mitochondrial in 2019; PubMed Scopus Google Scholar of the of indicate with a and in the of increased of was observed in HCN cells and increased and and data by miR-351-5p. previously reported that HCN cell death induced by miR-351-5p was an with the S. expression of adult hippocampal neural stem cells cell death an cell 2019; PubMed Scopus Google Scholar the effects of on HCN cell death were and inhibited the of and P. M. B.A. A. et the and of in PubMed Scopus Google Scholar death induced by miR-351-5p was in the presence of and and indicate that increased of miR-351-5p and decreased of Miro2 of Miro2 and miR-351-5p mitophagy and mitochondrial the role of in mitochondrial as mitochondrial and M. S. A. P. of mitochondrial by the Natl. Acad. Sci. USA. PubMed Scopus Google Scholar In the study, the of mitochondria increased in and HCN cells and miR-351-5p or HCN cells were mitophagy using and In the or and were and in or cells were the of the of we a mitophagy that increased the of the mitochondria with P. M. B.A. A. et the and of in PubMed Scopus Google Scholar The of the mitophagy in the was that in the was with siMiro2 also induced mitophagy The Pink1 and Parkin through that Pink1 and Parkin in and and suggest that Miro2 suppression by miR-351-5p mitophagy via Pink1 Parkin of Miro2 and miR-351-5p mitophagy in HCN and were with miR-351-5p, or siMiro2 and observed by mitochondria were by cell miR-351-5p and siMiro2 increased the of to the mitophagy HCN cells with miR-351-5p, or siMiro2 were with and the regions were observed as HCN cells with miR-351-5p, or siMiro2 were with mitophagy was through mitophagy and that Pink1 and Parkin in and the of Pink1 and Parkin by miR-351-5p. in the the with and HCN cells increased mitochondrial and was by the mitochondrial potential and to the reduction in the in the of the to from to and HCN cells a of a reduction in via the that miR-351-5p or siMiro2 decreased by miR-351-5p was by and The expression level of was increased and was decreased with miR-351-5p and siMiro2 and the of Miro2 expression by miR-351-5p mitochondrial by mitochondrial of Miro2 caused mitochondrial fission and and HCN cells with miR-351-5p and siMiro2 were with of HCN cells excessive mitochondrial fission in and The observed mitochondrial fission was potential was via Decreased mitochondrial potential in and HCN cells a of of was via a and cells were in and was miR-351-5p or siMiro2 decreased mitochondrial was on the of was as an of mitochondrial and fission factor and mitochondrial factor were by miR-351-5p and siMiro2. was as a was by in the the with miR-351-5p induced excessive mitochondrial fission in HCN of mitochondrial fission abolished induced by miR-351-5p via Miro2 by mitochondrial or mitochondrial fission a role in in HCN we cells with the mitochondrial fission A. T. J. of the mitochondrial its role in mitochondrial Cell. Full Text Full Text PDF PubMed Scopus Google Scholar of Mdivi-1 mitochondrial in the and and by miR-351-5p or siMiro2 mitochondrial fission completely miR-351-5p-induced cell death and The critical role of Miro2 in miR-351-5p-induced HCN cell death was through Miro2 using adenovirus in with miR-351-5p. HCN cells with and Miro2 were by in a and inhibited miR-351-5p-induced cell death to whereas in a in cell death and excessive mitochondrial fission induced by miR-351-5p and and mitochondrial as a and of Miro2 completely inhibited cell death and mitochondrial fission induced by insulin and data indicate that Miro2 is the target of miR-351-5p and HCN cell death through mitochondrial of mitochondrial fission inhibited induced by miR-351-5p via Miro2 by mitochondrial and Mdivi-1 is a mitochondrial fission that mitochondrial fission factor The effects of Mdivi-1 on mitochondrial fission induced by miR-351-5p or siMiro2 were observed and of mitochondrial potential was via was to mitochondrial Mdivi-1 inhibited induced through miR-351-5p and siMiro2 in a death was as in the the of Miro2 cell death and mitochondrial fission induced by miR-351-5p or insulin on HCN Miro2 was was using as a and completely miR-351-5p-induced cell death. and was and using with and miR-351-5p. and HCN cells were in an insulin in the presence of or death was by was using a in the the and Miro2 were in have reported that a neural progenitor the hippocampus from excessive cell death may be associated with neuronal observed AD T. Parylak S.L. Linker S.B. Gage F.H. The role of adult hippocampal neurogenesis in brain health and disease.Mol. Psychiatry. 2019; 24: 67-87Crossref PubMed Scopus (246) Google Scholar that dysregulation of miR-351-5p and its target Miro2 may the of HCN we data from the and to the Miro2 and AD. on the the an AD with AD and a were Miro2 were in the AD in the Miro2 was in the to the Miro2 expression in the hippocampal progenitor cells of the AD model was from and the model were Miro2 expression in progenitor cells in the hippocampus adult E.P. Flor-García M. Terreros-Roncal J. Rábano A. Cafini F. Pallas-Bazarra N. Ávila J. Llorens-Martín M. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease.Nat. Med. 2019; 25: 554-560Crossref PubMed Scopus (671) Google Scholar that Miro2 was decreased in the cells and Miro2 was decreased in the hippocampal cells The expression of miR-351-5p and Miro2 were by in the hippocampus of and AD model In the AD miR-351-5p was and Miro2 was to the potential of miR-351-5p and its target Miro2 expression in the of HCN cells in of miR-351-5p and its target Miro2 in the hippocampus is associated with adult neurogenesis and AD and data from the and were Miro2 The AD of including and the presence of amyloid and were and the expression of Miro2 in cells in the hippocampus of brain, and AD model were by using and were observed using a and of Miro2 were in cells using cell in dentate in the the cells cells from the mechanism of the miR-351-5p/Miro2 axis HCN cell death from the increased of miR-351-5p Miro2 in HCN Miro2 mitochondrial excessive mitophagy and HCN cell death, to mechanism of the miR-351-5p/Miro2 axis in adult an the of miR-351-5p, Miro2 in HCN Miro2 induced mitochondrial in excessive mitophagy and cell death in the HCN can to the in the and subsequent of hippocampal adult that the decline in neural progenitor cell may to the of including T. Parylak S.L. Linker S.B. Gage F.H. The role of adult hippocampal neurogenesis in brain health and disease.Mol. Psychiatry. 2019; 24: 67-87Crossref PubMed Scopus (246) Google Scholar stem cell in AD patients or a reduction in adult hippocampal neurogenesis in AD patients supports this E.P. Flor-García M. Terreros-Roncal J. Rábano A. Cafini F. Pallas-Bazarra N. Ávila J. Llorens-Martín M. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease.Nat. Med. 2019; 25: 554-560Crossref PubMed Scopus (671) Google Scholar data from the and a reduction in Miro2 in the hippocampus of the AD and and that AD is a chronic disease a a reduction in Miro2 expression can the of hippocampal a reduction of Miro2 in the cells in the hippocampus of AD model supports that Miro2 adult the indicate the of miR-351-5p and the of its target that the miR-351-5p/Miro2 axis the HCN cell reports that an in adult hippocampal neurogenesis is to and its potential as a therapeutic target A. A. adult hippocampal neurogenesis is to PubMed Scopus Google Adult hippocampal neurogenesis and cognitive memory and Neurosci. PubMed Scopus Google Scholar the miR-351-5p/Miro2 axis may be a target the of neural progenitor neurodegenerative of mitochondrial is to the of various including neuronal K. B.A. B. S. M.M. et and and cognitive deficits in of Alzheimer’s disease.Nat. Neurosci. 2019; 22: PubMed Scopus Google Scholar a of mitochondria are with plasticity cell death, and through including and of mitochondrial 2019; PubMed Scopus Google Scholar The indicate that suppression of Miro2 by miR-351-5p induced mitochondrial fission mitochondrial fission is a mitochondrial in mitophagy by S. P. and in mitochondrial 2018; Full Text Full Text PDF PubMed Scopus Google Scholar the suggest that excessive mitochondrial fission can to in loss of mitochondria and HCN cell death. is by the that cell death was by the mitochondrial fission Mdivi-1 a primary regulator of mitochondrial and ectopic expression of miR-351-5p-induced cell death was and mitochondrial was also and of Miro2 also cell death induced by insulin in HCN cells and indicate the role of Miro2 in in HCN cells through mitochondrial known to have a of and is involved in mitochondrial by mitochondrial and N. A. S.L. F. J. P. et mitochondrial and 2018; Full Text Full Text PDF PubMed Scopus Google Scholar and its factor mitochondrial fission through is a regulator of mitochondrial fission through 2016; PubMed Scopus Google Scholar that increased miR-351-5p by factors in HCN cells can the cell death owing to a mitochondrial fission and mitophagy in with the loss of of Miro2 and Miro2 were to have functional the in N. and mitochondrial and J. 2018; PubMed Scopus Google Scholar have functional and K. T. A. A. New of mitochondrial 2018; PubMed Scopus Google J. A. M. role mitochondrial in and of 2018; 19: PubMed Scopus Google Scholar suggest that miR-351-5p In the target miR-351-5p in its we that cell was observed in HCN cells expression in the data in and Although functional and Miro2 indicate that Miro2 potentially with in mitochondrial fission and in HCN death in HCN cells is known to be the by and et death of adult hippocampal neural stem cells insulin PubMed Scopus Google P. cell or PubMed Scopus Google Scholar miR-351-5p-induced cell death of increased and was by and In the miR-351-5p/Miro2 axis induced mitophagy and and mitophagy been previously reported is by Pink1 by Parkin and by the A. V. M. T. M.M. of Parkin is of a of Parkin PubMed Scopus Google Scholar of mitophagy through reduction of mitochondrial Parkin M. V. N. J. M. M. A. M. A. mitochondria Parkin and J. 2019; PubMed Scopus Google Scholar HCN cell death by the miR-351-5p/Miro2 axis was characterized by in the the of cell death largely miRNAs are in neurogenesis as and M. in neural from to PubMed Scopus Google S. and in neural stem cell PubMed Scopus Google J. A. T. J. A.R. et of in the of neurons in the adult 2016; Full Text Full Text PDF PubMed Scopus Google M. F. adult neurogenesis in the stem cell Neurosci. PubMed Scopus Google J. A. Gage F.H. from Neurosci. PubMed Scopus Google Scholar these miRNAs are involved in neurogenesis or neural and The indicate that miR-351-5p is a that cell and death HCN most of on the and death of HCN cells been from and is in adult The or miR-351-5p in HCN cells and the expression of miR-351-5p and mitochondrial Miro2 in the hippocampus of AD patients and AD model suggest that the miR-351-5p/Miro2 axis may in the contributing to the or of AD. miR-351-5p mitochondrial fission through Miro2 is a critical of cell death in rat adult HCN Collectively, these indicate that miR-351-5p and Miro2 are of cell death of the of dysregulation of hippocampal neurogenesis in and HCN cell and cells were in with and growth factor and insulin were to the HCN cells were with and and were from whereas were from was using to the and cells were the the HCN cells were with and were to Mdivi-1 was also to mitochondrial of HCN cells was by with and and were to the culture and cells were the observed were and a the cell death was cell death cell cell and cells were and in and cell were using the and with of The primary were as and The primary were to in and on the was using an were with and in The were using an and were on and were with and The were with model and were from and were by the and of cell HCN cells were on and S. T. T. of the by a PubMed Scopus Google Scholar were with miR-351-5p. were with a cells with miR-351-5p, or siMiro2 were with and and observed a of and were observed by the of HCN cells with miRNAs and siMiro2 were with a mitophagy to the HCN cells were with a of the HCN cells were with The of the mitophagy was using the cells were in and with miRNAs and were using as the cells were and with a using and were and of and and and The was of mitochondria were using the mitochondrial the mitochondrial HCN cells with were in a in or of mitochondrial was to The HCN cells were and was of mitochondrial cells were with and with a of cell regions in were mitochondrial using was to the of of miR-351-5p was with the by using the on the was as the The miR-351-5p was of was with was as the The Miro2 and were as of Miro2 and the of Miro2 were into the of the of by the of were using along with the miR-351-5p or into HCN The of and were The was using the using the were in and are as was with were the IntroductionAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the loss of neurons and synapses, synaptic dysfunction, mitochondrial dysfunction, and inflammatory responses, along with extracellular amyloid plaques and intracellular neurofibrillary tangles.1Scheltens P. Blennow K. Breteler M.M. de Strooper B. Frisoni G.B. Salloway S. Van der Flier W.M. Alzheimer’s disease.Lancet. 2016; 388: 505-517Abstract Full Text Full Text PDF PubMed Scopus (1801) Google Scholar Various factors are involved in the reduction of cognitive resilience linked with chronic neurodegenerative disease, including AD. New neurons are generated from multipotent neural progenitor cells in the dentate gyrus (DG) of the hippocampus throughout life, although neuroplasticity may be somewhat affected with age.2Boldrini M. Fulmore C.A. Tartt A.N. Simeon L.R. Pavlova I. Poposka V. Rosoklija G.B. Stankov A. Arango V. Dwork A.J. et al.Human hippocampal neurogenesis persists throughout aging.Cell Stem Cell. 2018; 22: 589-599.e5Abstract Full Text Full Text PDF PubMed Scopus (683) Google Scholar The hippocampus is one of the most affected areas in AD. Decreased neurogenesis in the hippocampus is a critical factor contributing to neurodegenerative defects owing to a declined neural progenitor pool caused by excessive cell death in the hippocampal neurogenic niche.3Toda T. Parylak S.L. Linker S.B. Gage F.H. The role of adult hippocampal neurogenesis in brain health and disease.Mol. Psychiatry. 2019; 24: 67-87Crossref PubMed Scopus (246) Google Scholar Recent reports strongly suggest that impaired adult neurogenesis in the hippocampus is a potentially relevant mechanism underlying memory deficits in AD.4Moreno-Jiménez E.P. Flor-García M. Terreros-Roncal J. Rábano A. Cafini F. Pallas-Bazarra N. Ávila J. Llorens-Martín M. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease.Nat. Med. 2019; 25: 554-560Crossref PubMed Scopus (671) Google ScholarAdult hippocampal neural progenitor (HCN) cells have previously been isolated from the adult rat brain by Gage group5Ray J. Peterson D.A. Schinstine M. Gage F.H. Proliferation, differentiation, and long-term culture of primary hippocampal neurons.Proc. Natl. Acad. Sci. USA. 1993; 90: 3602-3606Crossref PubMed Scopus (403) Google Scholar and differentiated into neurons, astrocytes, or oligodendrocytes in vitro and in vivo. HCN cells have also been proven to functionally integrate into existing neuronal networks in vivo.6Reynolds B.A. Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.Science. 1992; 255: 1707-1710Crossref PubMed Scopus (4510) Google Scholar Their proliferation and differentiation can be regulated by various exogenous and endogenous factors.7Palmer T.D. Markakis E.A. Willhoite A.R. Safar F. Gage F.H. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS.J. Neurosci. 1999; 19: 8487-8497Crossref PubMed Google Scholar Among these, insulin is known as a critical regulator of HCN cell death. Previously we reported that HCN cells undergo cell death with excessive in the of et death of adult hippocampal neural stem cells insulin PubMed Scopus Google Scholar to a of in neural stem cells the death of hippocampal neural stem cells induced by chronic S. S. et death of neural stem cells chronic decline of adult hippocampal neurogenesis and cognitive PubMed Scopus Google Scholar data indicate that HCN cells can be a model the of adult neurogenesis and cell death B. M. K. M. M. et and neurodegeneration in Neurosci. 22: PubMed Google Scholar the that HCN cell death largely in mitochondrial caused by the of and are known to be associated with K. B.A. B. S. M.M. et and and cognitive deficits in of Alzheimer’s disease.Nat. Neurosci. 2019; 22: PubMed Scopus Google Scholar a role in cells and of cell death, including and mitochondrial is regulated by mitochondrial as mitochondrial and of mitochondrial 2019; PubMed Scopus Google Scholar fission and mitochondrial and mitochondrial fission is by the guanosine triphosphatase whereas and and and N. K. and in mitochondrial via Sci. PubMed Scopus Google N. P. J. et a mitochondrial is in PubMed Scopus Google Scholar and mitochondrial in to Recent a functional mitochondrial and mitochondrial fission mitochondria to through S. P. and in mitochondrial 2018; Full Text Full Text PDF PubMed Scopus Google K. N. of mitophagy in and 2018; PubMed Scopus Google we and reported that microRNAs including miR-351-5p, expression death of HCN S. expression of adult hippocampal neural stem cells cell death an cell 2019; PubMed Scopus Google Scholar identified that increased of miR-351-5p HCN cell death the underlying HCN cell death miRNAs are endogenous in expression the level through to the of a with a miRNAs are involved in diverse including cell differentiation, and cell death. the nervous of is that miRNAs as critical of neuronal differentiation, and synaptic plasticity in the miRNAs in and of the nervous PubMed Scopus Google to the of miR-351-5p to HCN cell death, we that Miro2 be the target of miR-351-5p. is an on the mitochondrial in and Miro2. have that are involved in mitochondrial including and M. S. A. P. of mitochondrial by the Natl. Acad. Sci. USA. PubMed Scopus Google Scholar are involved in mitophagy through and by T. J. Parkin and mitochondrial Natl. Acad. Sci. USA. 2016; PubMed Scopus Google Scholar is also known that of in disease are to mitochondrial J. F. A. A. et in with and mitochondrial in 2019; PubMed Scopus Google the study, we on miR-351-5p and its target Miro2 to in HCN cell death to the of mitochondrial and the of these to AD.

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