Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2017

Open Access 01-12-2017 | Research article

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

Authors: Michal Arbel-Ornath, Eloise Hudry, Josiah R. Boivin, Tadafumi Hashimoto, Shuko Takeda, Kishore V. 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

Published in: Molecular Neurodegeneration | Issue 1/2017

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci. 2005;25:7278–87.CrossRefPubMedPubMedCentral
2.
Knowles RB, Wyart C, Buldyrev SV, Cruz L, Urbanc B, Hasselmo ME, Stanley HE, Hyman BT. Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer’s disease. Proc Natl Acad Sci U S A. 1999;96:5274–9.CrossRefPubMedPubMedCentral
3.
4.
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008;14:837–42.CrossRefPubMedPubMedCentral
5.
Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, et al. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci. 2010;30:2636–49.CrossRefPubMedPubMedCentral
6.
Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B, Konnerth A. Critical role of soluble amyloid-beta for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2012;109:8740–5.CrossRefPubMedPubMedCentral
7.
Viola KL, Velasco PT, Klein WL. Why Alzheimer’s is a disease of memory: the attack on synapses by A beta oligomers (ADDLs). J Nutr Health Aging. 2008;12:51S–7S.CrossRefPubMed
8.
Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ, Kim ML, Lee VM, et al. Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A. 2009;106:4012–7.CrossRefPubMedPubMedCentral
9.
Disterhoft JF, Moyer Jr JR, Thompson LT. The calcium rationale in aging and Alzheimer’s disease. Evidence from an animal model of normal aging. Ann N Y Acad Sci. 1994;747:382–406.CrossRefPubMed
10.
Khachaturian ZS. Calcium hypothesis of Alzheimer’s disease and brain aging. Ann N Y Acad Sci. 1994;747:1–11.CrossRefPubMed
11.
Chakroborty S, Stutzmann GE. Calcium channelopathies and Alzheimer’s disease: Insight into therapeutic success and failures. Eur J Pharmacol. 2013.
12.
13.
Smith IF, Green KN, LaFerla FM. Calcium dysregulation in Alzheimer’s disease: recent advances gained from genetically modified animals. Cell Calcium. 2005;38:427–37.CrossRefPubMed
14.
Reese LC, Laezza F, Woltjer R, Taglialatela G. Dysregulated phosphorylation of Ca(2+)/calmodulin-dependent protein kinase II-alpha in the hippocampus of subjects with mild cognitive impairment and Alzheimer’s disease. J Neurochem. 2011;119:791–804.CrossRefPubMedPubMedCentral
15.
Hudry E, Wu HY, Arbel-Ornath M, Hashimoto T, Matsouaka R, Fan Z, Spires-Jones TL, Betensky RA, Bacskai BJ, Hyman BT. Inhibition of the NFAT pathway alleviates amyloid beta neurotoxicity in a mouse model of Alzheimer’s disease. J Neurosci. 2012;32:3176–92.CrossRefPubMedPubMedCentral
16.
Malleret G, Haditsch U, Genoux D, Jones MW, Bliss TV, Vanhoose AM, Weitlauf C, Kandel ER, Winder DG, Mansuy IM. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell. 2001;104:675–86.CrossRefPubMed
17.
Kayyali US, Zhang W, Yee AG, Seidman JG, Potter H. Cytoskeletal changes in the brains of mice lacking calcineurin A alpha. J Neurochem. 1997;68:1668–78.CrossRefPubMed
18.
Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ. Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron. 2008;59:214–25.CrossRefPubMedPubMedCentral
19.
Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science. 2008;321:1686–9.CrossRefPubMed
20.
Grienberger C, Rochefort NL, Adelsberger H, Henning HA, Hill DN, Reichwald J, Staufenbiel M, Konnerth A. Staged decline of neuronal function in vivo in an animal model of Alzheimer’s disease. Nat Commun. 2012;3:774.CrossRefPubMedPubMedCentral
21.
Rudinskiy N, Hawkes JM, Betensky RA, Eguchi M, Yamaguchi S, Spires-Jones TL, Hyman BT. Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer’s disease. Nat Neurosci. 2012;15:1422–9.CrossRefPubMedPubMedCentral
22.
Stern EA, Bacskai BJ, Hickey GA, Attenello FJ, Lombardo JA, Hyman BT. Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques. J Neurosci. 2004;24:4535–40.CrossRefPubMed
23.
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005;309:476–81.CrossRefPubMedPubMedCentral
24.
Skoch J, Hickey GA, Kajdasz ST, Hyman BT, Bacskai BJ. In vivo imaging of amyloid-beta deposits in mouse brain with multiphoton microscopy. Methods Mol Biol. 2005;299:349–63.PubMed
25.
Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985;260:3440–50.PubMed
26.
Palmer AE, Tsien RY. Measuring calcium signaling using genetically targetable fluorescent indicators. Nat Protoc. 2006;1:1057–65.CrossRefPubMed
27.
Wu HY, Hudry E, Hashimoto T, Uemura K, Fan ZY, Berezovska O, Grosskreutz CL, Bacskai BJ, Hyman BT. Distinct dendritic spine and nuclear phases of calcineurin activation after exposure to amyloid-beta revealed by a novel fluorescence resonance energy transfer assay. J Neurosci. 2012;32:5298–309.CrossRefPubMedPubMedCentral
28.
Mehta PD, Pirttila T, Mehta SP, Sersen EA, Aisen PS, Wisniewski HM. Plasma and cerebrospinal fluid levels of amyloid beta proteins 1–40 and 1–42 in Alzheimer disease. Arch Neurol. 2000;57:100–5.CrossRefPubMed
29.
Nagai T, Yamada S, Tominaga T, Ichikawa M, Miyawaki A. Expanded dynamic range of fluorescent indicators for Ca(2+) by circularly permuted yellow fluorescent proteins. Proc Natl Acad Sci U S A. 2004;101:10554–9.CrossRefPubMedPubMedCentral
30.
31.
Tesli M, Skatun KC, Ousdal OT, Brown AA, Thoresen C, Agartz I, Melle I, Djurovic S, Jensen J, Andreassen OA. CACNA1C risk variant and amygdala activity in bipolar disorder, schizophrenia and healthy controls. PLoS ONE. 2013;8, e56970.CrossRefPubMedPubMedCentral
32.
Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S, Gordon-Smith K, Fraser C, Forty L, Russell E, et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry. 2010;15:1016–22.CrossRefPubMed
33.
34.
35.
Ilijic E, Guzman JN, Surmeier DJ. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson’s disease. Neurobiol Dis. 2011;43:364–71.CrossRefPubMedPubMedCentral
36.
Bezprozvanny I. Role of inositol 1,4,5-trisphosphate receptors in pathogenesis of Huntington’s disease and spinocerebellar ataxias. Neurochem Res. 2011;36:1186–97.CrossRefPubMedPubMedCentral
37.
38.
Bojarski L, Herms J, Kuznicki J. Calcium dysregulation in Alzheimer’s disease. Neurochem Int. 2008;52:621–33.CrossRefPubMed
39.
40.
Kopeikina KJ, Wegmann S, Pitstick R, Carlson GA, Bacskai BJ, Betensky RA, Hyman BT, Spires-Jones TL. Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy. PLoS ONE. 2013;8, e80834.CrossRefPubMedPubMedCentral
41.
Kuchibhotla KV, Wegmann S, Kopeikina KJ, Hawkes J, Rudinskiy N, Andermann ML, Spires-Jones TL, Bacskai BJ, Hyman BT. Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc Natl Acad Sci U S A. 2014;111:510–4.CrossRefPubMed
42.
Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007;27:2866–75.CrossRefPubMed
43.
44.
Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, Puolivali J, Lesne S, Ashe KH, Muchowski PJ, Mucke L. Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem. 2007;282:23818–28.CrossRefPubMed
45.
Howlett DR, Bowler K, Soden PE, Riddell D, Davis JB, Richardson JC, Burbidge SA, Gonzalez MI, Irving EA, Lawman A, et al. Abeta deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer’s disease. Histol Histopathol. 2008;23:67–76.PubMed
46.
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80.CrossRefPubMed
47.
DeKosky ST, Scheff SW, Styren SD. Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration. 1996;5:417–21.CrossRef
48.
West AE, Griffith EC, Greenberg ME. Regulation of transcription factors by neuronal activity. Nat Rev Neurosci. 2002;3:921–31.CrossRefPubMed
49.
50.
Kim JH, Anwyl R, Suh YH, Djamgoz MB, Rowan MJ. Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo. J Neurosci. 2001;21:1327–33.PubMed
51.
Texido L, Martin-Satue M, Alberdi E, Solsona C, Matute C. Amyloid beta peptide oligomers directly activate NMDA receptors. Cell Calcium. 2011;49:184–90.CrossRefPubMed
52.
Pellistri F, Bucciantini M, Relini A, Nosi D, Gliozzi A, Robello M, Stefani M. Nonspecific interaction of prefibrillar amyloid aggregates with glutamatergic receptors results in Ca2+ increase in primary neuronal cells. J Biol Chem. 2008;283:29950–60.CrossRefPubMedPubMedCentral
53.
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005;8:1051–8.CrossRefPubMed
54.
Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009;62:788–801.CrossRefPubMedPubMedCentral
55.
Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM. SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol. 2008;181:1107–16.CrossRefPubMedPubMedCentral
56.
Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK. Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron. 2008;58:871–83.CrossRefPubMedPubMedCentral
57.
Christensen RA, Shtifman A, Allen PD, Lopez JR, Querfurth HW. Calcium dyshomeostasis in beta-amyloid and tau-bearing skeletal myotubes. J Biol Chem. 2004;279:53524–32.CrossRefPubMed
58.
Demuro A, Parker I. Cytotoxicity of intracellular abeta42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. J Neurosci. 2013;33:3824–33.CrossRefPubMedPubMedCentral
59.
Peng J, Liang G, Inan S, Wu Z, Joseph DJ, Meng Q, Peng Y, Eckenhoff MF, Wei H. Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett. 2012;516:274–9.CrossRefPubMedPubMedCentral
60.
Osborn LM, Kamphuis W, Wadman WJ, Hol EM. Astrogliosis: An integral player in the pathogenesis of Alzheimer’s disease. Prog Neurobiol. 2016;144:121–41.CrossRefPubMed
61.
Drews A, Flint J, Shivji N, Jonsson P, Wirthensohn D, De Genst E, Vincke C, Muyldermans S, Dobson C, Klenerman D. Individual aggregates of amyloid beta induce temporary calcium influx through the cell membrane of neuronal cells. Sci Rep. 2016;6:31910.CrossRefPubMedPubMedCentral
62.
Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, Dziewczapolski G, Nakamura T, Cao G, Pratt AE, et al. Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A. 2013;110:E2518–27.CrossRefPubMedPubMedCentral
63.
Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science. 2009;323:1211–5.CrossRefPubMedPubMedCentral
64.
Takano T, Han X, Deane R, Zlokovic B, Nedergaard M. Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease. Ann N Y Acad Sci. 2007;1097:40–50.CrossRefPubMed
65.
Delekate A, Fuchtemeier M, Schumacher T, Ulbrich C, Foddis M, Petzold GC. Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model. Nat Commun. 2014;5:5422.CrossRefPubMed
Metadata
Title
Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain
Authors
Michal Arbel-Ornath
Eloise Hudry
Josiah R. Boivin
Tadafumi Hashimoto
Shuko Takeda
Kishore V. 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
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2017
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-017-0169-9

Other articles of this Issue 1/2017

Molecular Neurodegeneration 1/2017 Go to the issue

Research article

Blood cholesterol in late-life and cognitive decline: a longitudinal study of the Chinese elderly

Research article

Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury

Research article

Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer’s disease

Research article

Caspase vinyl sulfone small molecule inhibitors prevent axonal degeneration in human neurons and reverse cognitive impairment in Caspase-6-overexpressing mice

Erratum

Erratum to: Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

Research article

Autoimmune antibody decline in Parkinson’s disease and Multiple System Atrophy; a step towards immunotherapeutic strategies