Hippocampal stem cells promotes synaptic resistance to the dysfunctional impact of amyloid beta oligomers via secreted exosomes

Maria Micci, Balaji Krishnan, Elizabeth Bishop, Wen Ru Zhang, Jutatip Guptarak, Auston Grant, Olga Cain, Batbayar Tumurbaatar, Whitney Franklin, Claudia Marino, Steven Widen, Arjun Luthra, Steven G. Kernie, Giulio Taglialatela

Research output: Contribution to journalArticle

Abstract

Background: Adult hippocampal neurogenesis plays an important role in synaptic plasticity and cogntive function. We reported that higher numbers of neural stem cells (NSC) in the hippocampus of cognitively-intact individuals with high Alzheimer's disease (AD) pathology (plaques and tangles) is associated with decreased synaptic amyloid beta oligomers (Aβο), an event linked to onset of dementia in AD. While these findings suggest a link between NSC and synaptic resistance to Aβο, the involved mechanism remains to be determined. With this goal in mind, here we investigated the ability of exosomes secreted from hippocampal NSC to promote synaptic resilience to Aβo. Methods: Exosomes isolated from media of hippocampus NSC (NSC-exo) or mature hippocampal neuronal (MN-exo) cultures were delivered intracerebroventricularly (ICV) to mice before assessment of Aβο-induced suppression of hippocampal long-term potentiation (LTP) and memory deficits. Aβο binding to synapses was assessed in cultured hippocampal neurons and on synaptosomes isolated from hippocampal slices from wild type mice and from an inducible mouse model of NSC ablation (Nestin-δ-HSV-TK mice) treated with exosomes. Expression of CaMKII and of AMPA and NMDA glutamate receptor subunits in synaptosomes was measured by western blot. Small RNA Deep sequencing was performed to identify microRNAs enriched in NSC-exo as compared to MN-exo. Mimics of select miRNAs were injected ICV. Results: NSC-exo, but not MN-exo, abolished Aβo-induced suppression of LTP and subsequent memory deficits. Furthermore, in hippocampal slices and cultured neurons, NSC-exo significantly decreased Aβo binding to the synapse. Similarly, transgenic ablation of endogenous NSC increased synaptic Aβo binding, which was reversed by exogenous NSC-exo. Phosphorylation of synaptic CaMKII was increased by NSC-exo, while AMPA and NMDA receptors were not affected. Lastly, we identified a set of miRNAs enriched in NSC-exo that, when injected ICV, protected the synapses from Aβo-binding and Aβo-induced LTP inhibition. Conclusions: These results identify a novel mechanism linking NSC-exo and synaptic susceptibility to Aβo that may underscore cognitive resilience of certain individuals with increased neurogenesis in spite of AD neuropathology and unmask a novel target for the development of a new treatment concept for AD centered on promoting synaptic resilience to toxic amyloid proteins.

Original languageEnglish (US)
Article number25
JournalMolecular Neurodegeneration
Volume14
Issue number1
DOIs
StatePublished - Jun 14 2019

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Exosomes
Neural Stem Cells
Amyloid
Stem Cells
Long-Term Potentiation
Alzheimer Disease
MicroRNAs
Synapses
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Synaptosomes
Neurogenesis
Memory Disorders
N-Methyl-D-Aspartate Receptors
Hippocampus
RNA Sequence Analysis
Amyloidogenic Proteins
Neurons
High-Throughput Nucleotide Sequencing
Nestin
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

Keywords

  • Alzheimer's disease
  • Aβ oligomers
  • Exosomes
  • Neural stem cells
  • Synapses

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Hippocampal stem cells promotes synaptic resistance to the dysfunctional impact of amyloid beta oligomers via secreted exosomes. / Micci, Maria; Krishnan, Balaji; Bishop, Elizabeth; Zhang, Wen Ru; Guptarak, Jutatip; Grant, Auston; Cain, Olga; Tumurbaatar, Batbayar; Franklin, Whitney; Marino, Claudia; Widen, Steven; Luthra, Arjun; Kernie, Steven G.; Taglialatela, Giulio.

In: Molecular Neurodegeneration, Vol. 14, No. 1, 25, 14.06.2019.

Research output: Contribution to journalArticle

Micci, Maria ; Krishnan, Balaji ; Bishop, Elizabeth ; Zhang, Wen Ru ; Guptarak, Jutatip ; Grant, Auston ; Cain, Olga ; Tumurbaatar, Batbayar ; Franklin, Whitney ; Marino, Claudia ; Widen, Steven ; Luthra, Arjun ; Kernie, Steven G. ; Taglialatela, Giulio. / Hippocampal stem cells promotes synaptic resistance to the dysfunctional impact of amyloid beta oligomers via secreted exosomes. In: Molecular Neurodegeneration. 2019 ; Vol. 14, No. 1.
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abstract = "Background: Adult hippocampal neurogenesis plays an important role in synaptic plasticity and cogntive function. We reported that higher numbers of neural stem cells (NSC) in the hippocampus of cognitively-intact individuals with high Alzheimer's disease (AD) pathology (plaques and tangles) is associated with decreased synaptic amyloid beta oligomers (Aβο), an event linked to onset of dementia in AD. While these findings suggest a link between NSC and synaptic resistance to Aβο, the involved mechanism remains to be determined. With this goal in mind, here we investigated the ability of exosomes secreted from hippocampal NSC to promote synaptic resilience to Aβo. Methods: Exosomes isolated from media of hippocampus NSC (NSC-exo) or mature hippocampal neuronal (MN-exo) cultures were delivered intracerebroventricularly (ICV) to mice before assessment of Aβο-induced suppression of hippocampal long-term potentiation (LTP) and memory deficits. Aβο binding to synapses was assessed in cultured hippocampal neurons and on synaptosomes isolated from hippocampal slices from wild type mice and from an inducible mouse model of NSC ablation (Nestin-δ-HSV-TK mice) treated with exosomes. Expression of CaMKII and of AMPA and NMDA glutamate receptor subunits in synaptosomes was measured by western blot. Small RNA Deep sequencing was performed to identify microRNAs enriched in NSC-exo as compared to MN-exo. Mimics of select miRNAs were injected ICV. Results: NSC-exo, but not MN-exo, abolished Aβo-induced suppression of LTP and subsequent memory deficits. Furthermore, in hippocampal slices and cultured neurons, NSC-exo significantly decreased Aβo binding to the synapse. Similarly, transgenic ablation of endogenous NSC increased synaptic Aβo binding, which was reversed by exogenous NSC-exo. Phosphorylation of synaptic CaMKII was increased by NSC-exo, while AMPA and NMDA receptors were not affected. Lastly, we identified a set of miRNAs enriched in NSC-exo that, when injected ICV, protected the synapses from Aβo-binding and Aβo-induced LTP inhibition. Conclusions: These results identify a novel mechanism linking NSC-exo and synaptic susceptibility to Aβo that may underscore cognitive resilience of certain individuals with increased neurogenesis in spite of AD neuropathology and unmask a novel target for the development of a new treatment concept for AD centered on promoting synaptic resilience to toxic amyloid proteins.",
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author = "Maria Micci and Balaji Krishnan and Elizabeth Bishop and Zhang, {Wen Ru} and Jutatip Guptarak and Auston Grant and Olga Cain and Batbayar Tumurbaatar and Whitney Franklin and Claudia Marino and Steven Widen and Arjun Luthra and Kernie, {Steven G.} and Giulio Taglialatela",
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T1 - Hippocampal stem cells promotes synaptic resistance to the dysfunctional impact of amyloid beta oligomers via secreted exosomes

AU - Micci, Maria

AU - Krishnan, Balaji

AU - Bishop, Elizabeth

AU - Zhang, Wen Ru

AU - Guptarak, Jutatip

AU - Grant, Auston

AU - Cain, Olga

AU - Tumurbaatar, Batbayar

AU - Franklin, Whitney

AU - Marino, Claudia

AU - Widen, Steven

AU - Luthra, Arjun

AU - Kernie, Steven G.

AU - Taglialatela, Giulio

PY - 2019/6/14

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N2 - Background: Adult hippocampal neurogenesis plays an important role in synaptic plasticity and cogntive function. We reported that higher numbers of neural stem cells (NSC) in the hippocampus of cognitively-intact individuals with high Alzheimer's disease (AD) pathology (plaques and tangles) is associated with decreased synaptic amyloid beta oligomers (Aβο), an event linked to onset of dementia in AD. While these findings suggest a link between NSC and synaptic resistance to Aβο, the involved mechanism remains to be determined. With this goal in mind, here we investigated the ability of exosomes secreted from hippocampal NSC to promote synaptic resilience to Aβo. Methods: Exosomes isolated from media of hippocampus NSC (NSC-exo) or mature hippocampal neuronal (MN-exo) cultures were delivered intracerebroventricularly (ICV) to mice before assessment of Aβο-induced suppression of hippocampal long-term potentiation (LTP) and memory deficits. Aβο binding to synapses was assessed in cultured hippocampal neurons and on synaptosomes isolated from hippocampal slices from wild type mice and from an inducible mouse model of NSC ablation (Nestin-δ-HSV-TK mice) treated with exosomes. Expression of CaMKII and of AMPA and NMDA glutamate receptor subunits in synaptosomes was measured by western blot. Small RNA Deep sequencing was performed to identify microRNAs enriched in NSC-exo as compared to MN-exo. Mimics of select miRNAs were injected ICV. Results: NSC-exo, but not MN-exo, abolished Aβo-induced suppression of LTP and subsequent memory deficits. Furthermore, in hippocampal slices and cultured neurons, NSC-exo significantly decreased Aβo binding to the synapse. Similarly, transgenic ablation of endogenous NSC increased synaptic Aβo binding, which was reversed by exogenous NSC-exo. Phosphorylation of synaptic CaMKII was increased by NSC-exo, while AMPA and NMDA receptors were not affected. Lastly, we identified a set of miRNAs enriched in NSC-exo that, when injected ICV, protected the synapses from Aβo-binding and Aβo-induced LTP inhibition. Conclusions: These results identify a novel mechanism linking NSC-exo and synaptic susceptibility to Aβo that may underscore cognitive resilience of certain individuals with increased neurogenesis in spite of AD neuropathology and unmask a novel target for the development of a new treatment concept for AD centered on promoting synaptic resilience to toxic amyloid proteins.

AB - Background: Adult hippocampal neurogenesis plays an important role in synaptic plasticity and cogntive function. We reported that higher numbers of neural stem cells (NSC) in the hippocampus of cognitively-intact individuals with high Alzheimer's disease (AD) pathology (plaques and tangles) is associated with decreased synaptic amyloid beta oligomers (Aβο), an event linked to onset of dementia in AD. While these findings suggest a link between NSC and synaptic resistance to Aβο, the involved mechanism remains to be determined. With this goal in mind, here we investigated the ability of exosomes secreted from hippocampal NSC to promote synaptic resilience to Aβo. Methods: Exosomes isolated from media of hippocampus NSC (NSC-exo) or mature hippocampal neuronal (MN-exo) cultures were delivered intracerebroventricularly (ICV) to mice before assessment of Aβο-induced suppression of hippocampal long-term potentiation (LTP) and memory deficits. Aβο binding to synapses was assessed in cultured hippocampal neurons and on synaptosomes isolated from hippocampal slices from wild type mice and from an inducible mouse model of NSC ablation (Nestin-δ-HSV-TK mice) treated with exosomes. Expression of CaMKII and of AMPA and NMDA glutamate receptor subunits in synaptosomes was measured by western blot. Small RNA Deep sequencing was performed to identify microRNAs enriched in NSC-exo as compared to MN-exo. Mimics of select miRNAs were injected ICV. Results: NSC-exo, but not MN-exo, abolished Aβo-induced suppression of LTP and subsequent memory deficits. Furthermore, in hippocampal slices and cultured neurons, NSC-exo significantly decreased Aβo binding to the synapse. Similarly, transgenic ablation of endogenous NSC increased synaptic Aβo binding, which was reversed by exogenous NSC-exo. Phosphorylation of synaptic CaMKII was increased by NSC-exo, while AMPA and NMDA receptors were not affected. Lastly, we identified a set of miRNAs enriched in NSC-exo that, when injected ICV, protected the synapses from Aβo-binding and Aβo-induced LTP inhibition. Conclusions: These results identify a novel mechanism linking NSC-exo and synaptic susceptibility to Aβo that may underscore cognitive resilience of certain individuals with increased neurogenesis in spite of AD neuropathology and unmask a novel target for the development of a new treatment concept for AD centered on promoting synaptic resilience to toxic amyloid proteins.

KW - Alzheimer's disease

KW - Aβ oligomers

KW - Exosomes

KW - Neural stem cells

KW - Synapses

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