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



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.



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.



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.
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Michal
M
Arbel-Ornath
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Eloise
E
Hudry
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Josiah R
JR
Boivin
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.|Department of Neuropathology, The University of Tokyo, Tokyo, Japan.
Tadafumi
T
Hashimoto
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Shuko
S
Takeda
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.|Skirball Institute, NYU School of Medicine, New York, NY, 10016, USA.
Kishore V
KV
Kuchibhotla
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Steven
S
Hou
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Carli R
CR
Lattarulo
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Arianna M
AM
Belcher
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Naomi
N
Shakerdge
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Pariss B
PB
Trujillo
Department of Biostatistics, Harvard School of Public Health, 50 Staniford Street, Boston, MA, USA.
Alona
A
Muzikansky
Department of Biostatistics, Harvard School of Public Health, 50 Staniford Street, Boston, MA, USA.
Rebecca A
RA
Betensky
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Bradley T
BT
Hyman
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA. bbacskai@partners.org.
Brian J
BJ
Bacskai
D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D013569:Synapses / Q000187:drug effects / Q000473:pathology*
D016229:Amyloid beta-Peptides
Alzheimer’s disease; Amyloid β oligomers; Calcium; In vivo imaging