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Mol Neurodegener. 2017 Mar 21;12(1):27. doi: 10.1186/s13024-017-0169-9.

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

Author information

1
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
2
Department of Neuropathology, The University of Tokyo, Tokyo, Japan.
3
Skirball Institute, NYU School of Medicine, New York, NY, 10016, USA.
4
Department of Biostatistics, Harvard School of Public Health, 50 Staniford Street, Boston, MA, USA.
5
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA. bbacskai@partners.org.

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.

KEYWORDS:

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

PMID:
28327181
PMCID:
PMC5361864
DOI:
10.1186/s13024-017-0169-9
[Indexed for MEDLINE]
Free PMC Article

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