Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain

Michal Arbel-Ornath, Eloise Hudry, Josiah R. Boivin, Tadafumi Hashimoto, Shuko Takeda, Kishore Kuchibhotla, Steven Hou, Carli R. Lattarulo, Arianna M. Belcher, Naomi Shakerdge, Pariss B. Trujillo, Alona Muzikansky, Rebecca A. Betensky, Bradley T. Hyman, Brian J. Bacskai

Research output: Contribution to journalArticle

Abstract

Background: Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer’s disease (AD), and previous studies in AD transgenic mice suggest that calcium dysregulation may contribute to these pathological effects. Even though AD mouse models remain a valuable resource to investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, and fragments of amyloid precursor protein (APP) complicate the interpretation of the phenotypes. Method: To explore the specific contribution of soluble oligomeric Aβ (oAβ) to calcium dyshomeostasis and synaptic morphological changes, we acutely exposed the healthy mouse brain, at 3 to 6 months of age, to naturally occurring soluble oligomers and investigated their effect on calcium levels using in vivo multiphoton imaging. Results: We observed a dramatic increase in the levels of neuronal resting calcium, which was dependent upon extracellular calcium influx and activation of NMDA receptors. Ryanodine receptors, previously implicated in AD models, did not appear to be primarily involved using this experimental setting. We used the high resolution cortical volumes acquired in-vivo to measure the effect on synaptic densities and observed that, while spine density remained stable within the first hour of oAβ exposure, a significant decrease in the number of dendritic spines was observed 24 h post treatment, despite restoration of intraneuronal calcium levels at this time point. Conclusions: These observations demonstrate a specific effect of oAβ on NMDA-mediated calcium influx, which triggers synaptic collapse in vivo. Moreover, this work leverages a method to quantitatively measure calcium concentration at the level of neuronal processes, cell bodies and single synaptic elements repeatedly and thus can be applicable to testing putative drugs and/or other intervention methodologies.

Original languageEnglish (US)
Article number27
JournalMolecular Neurodegeneration
Volume12
Issue number1
DOIs
StatePublished - Mar 21 2017
Externally publishedYes

Fingerprint

Amyloid
Synapses
Calcium
Brain
Alzheimer Disease
Serum Amyloid A Protein
Dendritic Spines
Ryanodine Receptor Calcium Release Channel
Amyloid beta-Protein Precursor
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Transgenic Mice
Spine
Phenotype
Pharmaceutical Preparations

Keywords

  • Alzheimer’s disease
  • Amyloid β oligomers
  • Calcium
  • In vivo imaging

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. / Arbel-Ornath, Michal; Hudry, Eloise; Boivin, Josiah R.; Hashimoto, Tadafumi; Takeda, Shuko; Kuchibhotla, Kishore; Hou, Steven; Lattarulo, Carli R.; Belcher, Arianna M.; Shakerdge, Naomi; Trujillo, Pariss B.; Muzikansky, Alona; Betensky, Rebecca A.; Hyman, Bradley T.; Bacskai, Brian J.

In: Molecular Neurodegeneration, Vol. 12, No. 1, 27, 21.03.2017.

Research output: Contribution to journalArticle

Arbel-Ornath, M, Hudry, E, Boivin, JR, Hashimoto, T, Takeda, S, Kuchibhotla, K, Hou, S, Lattarulo, CR, Belcher, AM, Shakerdge, N, Trujillo, PB, Muzikansky, A, Betensky, RA, Hyman, BT & Bacskai, BJ 2017, 'Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain', Molecular Neurodegeneration, vol. 12, no. 1, 27. https://doi.org/10.1186/s13024-017-0169-9
Arbel-Ornath, Michal ; Hudry, Eloise ; Boivin, Josiah R. ; Hashimoto, Tadafumi ; Takeda, Shuko ; Kuchibhotla, Kishore ; Hou, Steven ; Lattarulo, Carli R. ; Belcher, Arianna M. ; Shakerdge, Naomi ; Trujillo, Pariss B. ; Muzikansky, Alona ; Betensky, Rebecca A. ; Hyman, Bradley T. ; Bacskai, Brian J. / Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. In: Molecular Neurodegeneration. 2017 ; Vol. 12, No. 1.
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abstract = "Background: Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer’s disease (AD), and previous studies in AD transgenic mice suggest that calcium dysregulation may contribute to these pathological effects. Even though AD mouse models remain a valuable resource to investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, and fragments of amyloid precursor protein (APP) complicate the interpretation of the phenotypes. Method: To explore the specific contribution of soluble oligomeric Aβ (oAβ) to calcium dyshomeostasis and synaptic morphological changes, we acutely exposed the healthy mouse brain, at 3 to 6 months of age, to naturally occurring soluble oligomers and investigated their effect on calcium levels using in vivo multiphoton imaging. Results: We observed a dramatic increase in the levels of neuronal resting calcium, which was dependent upon extracellular calcium influx and activation of NMDA receptors. Ryanodine receptors, previously implicated in AD models, did not appear to be primarily involved using this experimental setting. We used the high resolution cortical volumes acquired in-vivo to measure the effect on synaptic densities and observed that, while spine density remained stable within the first hour of oAβ exposure, a significant decrease in the number of dendritic spines was observed 24 h post treatment, despite restoration of intraneuronal calcium levels at this time point. Conclusions: These observations demonstrate a specific effect of oAβ on NMDA-mediated calcium influx, which triggers synaptic collapse in vivo. Moreover, this work leverages a method to quantitatively measure calcium concentration at the level of neuronal processes, cell bodies and single synaptic elements repeatedly and thus can be applicable to testing putative drugs and/or other intervention methodologies.",
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AU - Arbel-Ornath, Michal

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AU - Boivin, Josiah R.

AU - Hashimoto, Tadafumi

AU - Takeda, Shuko

AU - Kuchibhotla, Kishore

AU - Hou, Steven

AU - Lattarulo, Carli R.

AU - Belcher, Arianna M.

AU - Shakerdge, Naomi

AU - Trujillo, Pariss B.

AU - Muzikansky, Alona

AU - Betensky, Rebecca A.

AU - Hyman, Bradley T.

AU - Bacskai, Brian J.

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N2 - Background: Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer’s disease (AD), and previous studies in AD transgenic mice suggest that calcium dysregulation may contribute to these pathological effects. Even though AD mouse models remain a valuable resource to investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, and fragments of amyloid precursor protein (APP) complicate the interpretation of the phenotypes. Method: To explore the specific contribution of soluble oligomeric Aβ (oAβ) to calcium dyshomeostasis and synaptic morphological changes, we acutely exposed the healthy mouse brain, at 3 to 6 months of age, to naturally occurring soluble oligomers and investigated their effect on calcium levels using in vivo multiphoton imaging. Results: We observed a dramatic increase in the levels of neuronal resting calcium, which was dependent upon extracellular calcium influx and activation of NMDA receptors. Ryanodine receptors, previously implicated in AD models, did not appear to be primarily involved using this experimental setting. We used the high resolution cortical volumes acquired in-vivo to measure the effect on synaptic densities and observed that, while spine density remained stable within the first hour of oAβ exposure, a significant decrease in the number of dendritic spines was observed 24 h post treatment, despite restoration of intraneuronal calcium levels at this time point. Conclusions: These observations demonstrate a specific effect of oAβ on NMDA-mediated calcium influx, which triggers synaptic collapse in vivo. Moreover, this work leverages a method to quantitatively measure calcium concentration at the level of neuronal processes, cell bodies and single synaptic elements repeatedly and thus can be applicable to testing putative drugs and/or other intervention methodologies.

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