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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2017

Open Access 01-12-2017 | Research article

Abnormal dendritic calcium activity and synaptic depotentiation occur early in a mouse model of Alzheimer’s disease

Authors: Yang Bai, Miao Li, Yanmei Zhou, Lei Ma, Qian Qiao, Wanling Hu, Wei Li, Zachary Patrick Wills, Wen-Biao Gan

Published in: Molecular Neurodegeneration | Issue 1/2017

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Abstract

Background

Alzheimer’s disease (AD) is characterized by amyloid deposition, tangle formation as well as synapse loss. Synaptic abnormalities occur early in the pathogenesis of AD. Identifying early synaptic abnormalities and their underlying mechanisms is likely important for the prevention and treatment of AD.

Methods

We performed in vivo two-photon calcium imaging to examine the activities of somas, dendrites and dendritic spines of layer 2/3 pyramidal neurons in the primary motor cortex in the APPswe/PS1dE9 mouse model of AD and age-matched wild type control mice. We also performed calcium imaging to determine the effect of Aβ oligomers on dendritic calcium activity. In addition, structural and functional two-photon imaging were used to examine the link between abnormal dendritic calcium activity and changes in dendritic spine size in the AD mouse model.

Results

We found that somatic calcium activities of layer 2/3 neurons were significantly lower in the primary motor cortex of 3-month-old APPswe/PS1dE9 mice than in wild type mice during quiet resting, but not during running on a treadmill. Notably, a significantly larger fraction of apical dendrites of layer 2/3 pyramidal neurons showed calcium transients with abnormally long duration and high peak amplitudes during treadmill running in AD mice. Administration of Aβ oligomers into the brain of wild type mice also induced abnormal dendritic calcium transients during running. Furthermore, we found that the activity and size of dendritic spines were significantly reduced on dendritic branches with abnormally prolonged dendritic calcium transients in AD mice.

Conclusion

Our findings show that abnormal dendritic calcium transients and synaptic depotentiation occur before amyloid plaque formation in the motor cortex of the APPswe/PS1dE9 mouse model of AD. Dendritic calcium transients with abnormally long durations and high amplitudes could be induced by soluble Aβ oligomers and contribute to synaptic deficits in the early pathogenesis of AD.
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Literature
1.
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
2.
Masliah E, Crews L, Hansen L. Synaptic remodeling during aging and in Alzheimer's disease. J Alzheimers Dis. 2006;9:91–9.CrossRefPubMed
3.
Scheff SW, Price DA. Synapse loss in the temporal lobe in Alzheimer's disease. Ann Neurol. 1993;33:190–9.CrossRefPubMed
4.
5.
Scheff SW, Price DA, Schmitt FA, Mufson EJ. Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neurobiol Aging. 2006;27:1372–84.CrossRefPubMed
6.
Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology. 2007;68:1501–8.CrossRefPubMed
7.
Honer WG. Pathology of presynaptic proteins in Alzheimer's disease: more than simple loss of terminals. Neurobiol Aging. 2003;24:1047–62.CrossRefPubMed
8.
Jacobsen JS, CC W, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006;103:5161–6.CrossRefPubMedPubMedCentral
9.
CC W, Chawla F, Games D, Rydel RE, Freedman S, Schenk D, Young WG, Morrison JH, Bloom FE. Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: digital morphometric analyses. Proc Natl Acad Sci U S A. 2004;101:7141–6.CrossRef
10.
Reddy PH, Mani G, Park BS, Jacques J, Murdoch G, Whetsell W Jr, Kaye J, Manczak M. Differential loss of synaptic proteins in Alzheimer's disease: implications for synaptic dysfunction. J Alzheimers Dis. 2005;7:103–17. discussion 173-180CrossRefPubMed
11.
Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004;62:925–31.CrossRefPubMed
12.
Maras PM, Molet J, Chen Y, Rice C, Ji SG, Solodkin A, Baram TZ. Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress. Mol Psychiatry. 2014;19:811–22.CrossRefPubMedPubMedCentral
13.
Vanleeuwen JE, Penzes P. Long-term perturbation of spine plasticity results in distinct impairments of cognitive function. J Neurochem. 2012;123:781–9.CrossRefPubMedPubMedCentral
14.
Albers MW, Gilmore GC, Kaye J, Murphy C, Wingfield A, Bennett DA, Boxer AL, Buchman AS, Cruickshanks KJ, Devanand DP, et al. At the interface of sensory and motor dysfunctions and Alzheimer's disease. Alzheimers Dement. 2015;11:70–98.CrossRefPubMed
15.
Chainay H, Louarn C, Humphreys GW. Ideational action impairments in Alzheimer's disease. Brain Cogn. 2006;62:198–205.CrossRefPubMed
16.
Hebert LE, Bienias JL, McCann JJ, Scherr PA, Wilson RS, Evans DA. Upper and lower extremity motor performance and functional impairment in Alzheimer's disease. Am J Alzheimers Dis Other Demen. 2010;25:425–31.CrossRefPubMedPubMedCentral
17.
Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fulop L, Penke B, Zilberter Y, Harkany T, Pitkanen A, Tanila H. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci. 2009;29:3453–62.CrossRefPubMed
18.
Quiroz YT, Budson AE, Celone K, Ruiz A, Newmark R, Castrillon G, Lopera F, Stern CE. Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease. Ann Neurol. 2010;68:865–75.CrossRefPubMedPubMedCentral
19.
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
20.
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
21.
Lefort S, Tomm C, Floyd Sarria JC, Petersen CC. The excitatory neuronal network of the C2 barrel column in mouse primary somatosensory cortex. Neuron. 2009;61:301–16.CrossRefPubMed
22.
23.
Grutzendler J, Helmin K, Tsai J, Gan WB. Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer's disease. Ann N Y Acad Sci. 2007;1097:30–9.CrossRefPubMed
24.
Perez-Cruz C, Nolte MW, van Gaalen MM, Rustay NR, Termont A, Tanghe A, Kirchhoff F, Ebert U. Reduced spine density in specific regions of CA1 pyramidal neurons in two transgenic mouse models of Alzheimer's disease. J Neurosci. 2011;31:3926–34.CrossRefPubMed
25.
del Valle J, Bayod S, Camins A, Beas-Zarate C, Velazquez-Zamora DA, Gonzalez-Burgos I, Pallas M. Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer's disease. J Alzheimers Dis. 2012;32:233–40.PubMed
26.
Tsai J, Grutzendler J, Duff K, Gan WB. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci. 2004;7:1181–3.CrossRefPubMed
27.
Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, GQ Y, Kreitzer A, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007;55:697–711.CrossRefPubMed
28.
Koukouli F, Rooy M, Maskos U. Early and progressive deficit of neuronal activity patterns in a model of local amyloid pathology in mouse prefrontal cortex. Aging (Albany NY). 2016;8:3430–49.CrossRef
29.
Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol. 1999;155:853–62.CrossRefPubMedPubMedCentral
30.
Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000;283:1571–7.CrossRefPubMed
31.
32.
Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, et al. Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem. 1999;274:6483–92.CrossRefPubMed
33.
Mucke L, Masliah E, GQ Y, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000;20:4050–8.PubMed
34.
Busche MA, Kekus M, Adelsberger H, Noda T, Forstl H, Nelken I, Konnerth A. Rescue of long-range circuit dysfunction in Alzheimer's disease models. Nat Neurosci. 2015;18:1623–30.CrossRefPubMed
35.
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
36.
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
37.
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
38.
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
39.
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
40.
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
41.
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
42.
Chen TW, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A, Schreiter ER, Kerr RA, Orger MB, Jayaraman V, et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature. 2013;499:295–300.CrossRefPubMedPubMedCentral
43.
44.
Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng. 2001;17:157–65.CrossRefPubMed
45.
Borchelt DR, Davis J, Fischer M, Lee MK, Slunt HH, Ratovitsky T, Regard J, Copeland NG, Jenkins NA, Sisodia SS, Price DL. A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet Anal. 1996;13:159–63.CrossRefPubMed
46.
Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP. Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis. 2006;24:516–24.CrossRefPubMed
47.
Heiss JK, Barrett J, Yu Z, Haas LT, Kostylev MA, Strittmatter SM. Early activation of experience-independent dendritic spine turnover in a mouse model of Alzheimer's disease. Cereb Cortex. 2017;27:3660–74.PubMed
48.
Zhao YJ, Sivaji S, Chiang MC, Ali H, Zukowski M, Ali D, Kennedy B, Sklyar A, Cheng A, Guo ZH, et al. Amyloid Beta peptides block new synapse assembly by Nogo receptor-mediated inhibition of T-type calcium channels. Neuron. 2017;96:355–72.CrossRefPubMed
49.
50.
Yang G, Lai CSW, Cichon J, Ma L, Li W, Gan WB. Sleep promotes branch-specific formation of dendritic spines after learning. Science. 2014;344:1173–8.CrossRefPubMedPubMedCentral
51.
Li CX, Waters RS. Organization of the mouse motor cortex studied by retrograde tracing and intracortical microstimulation (ICMS) mapping. Can J Neurol Sci. 1991;18:28–38.CrossRefPubMed
52.
Helmchen F, Imoto K, Sakmann B. Ca2+ buffering and action potential-evoked Ca2+ signaling in dendrites of pyramidal neurons. Biophys J. 1996;70:1069–81.CrossRefPubMedPubMedCentral
53.
Svoboda K, Helmchen F, Denk W, Tank DW. Spread of dendritic excitation in layer 2/3 pyramidal neurons in rat barrel cortex in vivo. Nat Neurosci. 1999;2:65–73.CrossRefPubMed
54.
Myoga MH, Beierlein M, Regehr WG. Somatic spikes regulate dendritic signaling in small neurons in the absence of backpropagating action potentials. J Neurosci. 2009;29:7803–14.CrossRefPubMedPubMedCentral
55.
Golding NL, Staff NP, Spruston N. Dendritic spikes as a mechanism for cooperative long-term potentiation. Nature. 2002;418:326–31.CrossRefPubMed
56.
Humeau Y, Luthi A. Dendritic calcium spikes induce bi-directional synaptic plasticity in the lateral amygdala. Neuropharmacology. 2007;52:234–43.CrossRefPubMed
57.
Waters J, Helmchen F. Boosting of action potential backpropagation by neocortical network activity in vivo. J Neurosci. 2004;24:11127–36.CrossRefPubMed
58.
NL X, Harnett MT, Williams SR, Huber D, O'Connor DH, Svoboda K, Magee JC. Nonlinear dendritic integration of sensory and motor input during an active sensing task. Nature. 2012;492:247–51.CrossRef
59.
Grienberger C, Chen X, Konnerth A. NMDA receptor-dependent multidendrite ca(2+) spikes required for hippocampal burst firing in vivo. Neuron. 2014;81:1274–81.CrossRefPubMed
60.
Palmer LM, Shai AS, Reeve JE, Anderson HL, Paulsen O, Larkum ME. NMDA spikes enhance action potential generation during sensory input. Nat Neurosci. 2014;17:383–90.CrossRefPubMed
61.
Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352–7.CrossRefPubMed
62.
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
63.
Woods NK, Padmanabhan J. Neuronal calcium signaling and Alzheimer's disease. Adv Exp Med Biol. 2012;740:1193–217.CrossRefPubMed
64.
Arbel-Ornath M, Hudry E, Boivin JR, Hashimoto T, Takeda S, Kuchibhotla KV, Hou S, Lattarulo CR, Belcher AM, Shakerdge N, et al. Soluble oligomeric amyloid-beta induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. Mol Neurodegener. 2017;12:27.CrossRefPubMedPubMedCentral
65.
Dinamarca MC, Colombres M, Cerpa W, Bonansco C, Inestrosa NC. Beta-amyloid oligomers affect the structure and function of the postsynaptic region: role of the Wnt signaling pathway. Neurodegener Dis. 2008;5:149–52.CrossRefPubMed
66.
Holthoff K, Kovalchuk Y, Yuste R, Konnerth A. Single-shock LTD by local dendritic spikes in pyramidal neurons of mouse visual cortex. J Physiol. 2004;560:27–36.CrossRefPubMedPubMedCentral
67.
Kampa BM, Letzkus JJ, Stuart GJ. Requirement of dendritic calcium spikes for induction of spike-timing-dependent synaptic plasticity. J Physiol. 2006;574:283–90.CrossRefPubMedPubMedCentral
68.
Lisman J, Spruston N. Postsynaptic depolarization requirements for LTP and LTD: a critique of spike timing-dependent plasticity. Nat Neurosci. 2005;8:839–41.CrossRefPubMed
69.
Nevian T, Sakmann B. Single spine Ca2+ signals evoked by coincident EPSPs and backpropagating action potentials in spiny stellate cells of layer 4 in the juvenile rat somatosensory barrel cortex. J Neurosci. 2004;24:1689–99.CrossRefPubMed
70.
Sheffield ME, Dombeck DA. Calcium transient prevalence across the dendritic arbour predicts place field properties. Nature. 2015;517:200–4.CrossRefPubMed
71.
72.
Zeiger W, Vetrivel KS, Buggia-Prevot V, Nguyen PD, Wagner SL, Villereal ML, Thinakaran G. Ca2+ influx through store-operated Ca2+ channels reduces Alzheimer disease beta-amyloid peptide secretion. J Biol Chem. 2013;288:26955–66.CrossRefPubMedPubMedCentral
73.
74.
Jensen LE, Bultynck G, Luyten T, Amijee H, Bootman MD, Roderick HL. Alzheimer's disease-associated peptide Abeta42 mobilizes ER ca(2+) via InsP3R-dependent and -independent mechanisms. Front Mol Neurosci. 2013;6:36.CrossRefPubMedPubMedCentral
75.
Mattson MP. ER calcium and Alzheimer's disease: in a state of flux. Science signaling 2010;3:pe10.
76.
Small DH. Dysregulation of calcium homeostasis in Alzheimer's disease. Neurochem Res. 2009;34:1824–9.CrossRefPubMed
77.
Metadata
Title
Abnormal dendritic calcium activity and synaptic depotentiation occur early in a mouse model of Alzheimer’s disease
Authors
Yang Bai
Miao Li
Yanmei Zhou
Lei Ma
Qian Qiao
Wanling Hu
Wei Li
Zachary Patrick Wills
Wen-Biao Gan
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/s13024-017-0228-2

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