{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:37:54Z","timestamp":1791815874783,"version":"4.3.4"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G067515N"],"award-info":[{"award-number":["G067515N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G048917N"],"award-info":[{"award-number":["G048917N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease (AD) is the most common form of dementia in the elderly. According to the amyloid hypothesis, the accumulation and deposition of amyloid-beta (A\u03b2) peptides play a key role in AD. Soluble A\u03b2 (sA\u03b2) oligomers were shown to be involved in pathological hypersynchronisation of brain resting-state networks in different transgenic developmental-onset mouse models of amyloidosis. However, the impact of protein overexpression during brain postnatal development may cause additional phenotypes unrelated to AD. To address this concern, we investigated sA\u03b2 effects on functional resting-state networks in transgenic mature-onset amyloidosis Tet-Off APP (TG) mice. TG mice and control littermates were raised on doxycycline (DOX) diet from 3d up to 3\u2009m of age to suppress transgenic A\u03b2 production. Thereafter, longitudinal resting-state functional MRI was performed on a 9.4\u2009T MR-system starting from week 0 (3\u2009m old mice) up to 28w post DOX treatment. Ex-vivo immunohistochemistry and ELISA analysis was performed to assess the development of amyloid pathology. Functional Connectivity (FC) analysis demonstrated early abnormal hypersynchronisation in the TG mice compared to the controls at 8w post DOX treatment, particularly across regions of the default mode-like network, known to be affected in AD. Ex-vivo analyses performed at this time point confirmed a 20-fold increase in total sA\u03b2 levels preceding the apparition of A\u03b2 plaques and inflammatory responses in the TG mice compared to the controls. On the contrary at week 28, TG mice showed an overall hypoconnectivity, coinciding with a widespread deposition of A\u03b2 plaques in the brain. By preventing developmental influence of APP and\/or sA\u03b2 during brain postnatal development, we demonstrated FC abnormalities potentially driven by sA\u03b2 neurotoxicity on resting-state neuronal networks in mature-induced TG mice. Thus, the Tet-Off APP mouse model could be a powerful tool while used as a mature-onset model to shed light into amyloidosis mechanisms in AD.<\/jats:p>","DOI":"10.1186\/s40478-019-0810-7","type":"journal-article","created":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T11:02:49Z","timestamp":1573729369000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis"],"prefix":"10.1186","volume":"7","author":[{"given":"In\u00e8s R. H.","family":"Ben-Nejma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneta J.","family":"Keliris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmijn","family":"Daans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Ponsaerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marleen","family":"Verhoye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemie","family":"Van der Linden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6732-1261","authenticated-orcid":false,"given":"Georgios A.","family":"Keliris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,14]]},"reference":[{"key":"810_CR1","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.nbd.2018.11.010","volume":"124","author":"C Anckaerts","year":"2018","unstructured":"Anckaerts C et al (2018) Early functional connectivity deficits and progressive microstructural alterations in the TgF344-AD rat model of Alzheimer\u2019s disease: a longitudinal MRI study. Neurobiol Dis 124:93\u2013107","journal-title":"Neurobiol Dis"},{"key":"810_CR2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s40478-015-0187-1","volume":"3","author":"T Arendt","year":"2015","unstructured":"Arendt T et al (2015) Early neurone loss in Alzheimer\u2019s disease: cortical or subcortical? Acta Neuropathol Commun 3:10","journal-title":"Acta Neuropathol Commun"},{"key":"810_CR3","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.dadm.2017.03.007","volume":"8","author":"A Badhwar","year":"2017","unstructured":"Badhwar A et al (2017) Resting-state network dysfunction in Alzheimer\u2019s disease: A systematic review and meta-analysis. Alzheimers Dement (Amst) 8:73\u201385","journal-title":"Alzheimers Dement (Amst)"},{"issue":"13","key":"810_CR4","doi-asserted-by":"publisher","first-page":"5719","DOI":"10.1523\/JNEUROSCI.22-13-05719.2002","volume":"22","author":"R Bejar","year":"2002","unstructured":"Bejar R et al (2002) Transgenic calmodulin-dependent protein kinase II activation: dose-dependent effects on synaptic plasticity, learning, and memory. J Neurosci 22(13):5719\u20135726","journal-title":"J Neurosci"},{"issue":"3","key":"810_CR5","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/nn.3028","volume":"15","author":"I Benilova","year":"2012","unstructured":"Benilova I, Karran E, De Strooper B (2012) The toxic Abeta oligomer and Alzheimer\u2019s disease: an emperor in need of clothes. Nat Neurosci 15(3):349\u2013357","journal-title":"Nat Neurosci"},{"issue":"9","key":"810_CR6","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1016\/j.neurobiolaging.2011.07.003","volume":"33","author":"MA Binnewijzend","year":"2012","unstructured":"Binnewijzend MA et al (2012) Resting-state fMRI changes in Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 33(9):2018\u20132028","journal-title":"Neurobiol Aging"},{"key":"810_CR7","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.1910340409","volume-title":"Functional connectivity in the motor cortex of resting human brain using Echo-planar MRI","author":"B Biswal","year":"1995","unstructured":"Biswal B (1995) Functional connectivity in the motor cortex of resting human brain using Echo-planar MRI"},{"issue":"7","key":"810_CR8","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1056\/NEJM200008173430701","volume":"343","author":"SY Bookheimer","year":"2000","unstructured":"Bookheimer SY et al (2000) Patterns of brain activation in people at risk for Alzheimer\u2019s disease. N Engl J Med 343(7):450\u2013456","journal-title":"N Engl J Med"},{"issue":"11","key":"810_CR9","doi-asserted-by":"publisher","first-page":"3826","DOI":"10.1523\/JNEUROSCI.5171-13.2014","volume":"34","author":"HA Born","year":"2014","unstructured":"Born HA et al (2014) Genetic suppression of transgenic APP rescues Hypersynchronous network activity in a mouse model of Alzeimer\u2019s disease. J Neurosci 34(11):3826\u20133840","journal-title":"J Neurosci"},{"key":"810_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1196\/annals.1440.011","volume":"1124","author":"RL Buckner","year":"2008","unstructured":"Buckner RL, Andrews-Hanna JR, Schacter DL (2008) The brain\u2019s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci 1124:1\u201338","journal-title":"Ann N Y Acad Sci"},{"issue":"34","key":"810_CR11","doi-asserted-by":"publisher","first-page":"7709","DOI":"10.1523\/JNEUROSCI.2177-05.2005","volume":"25","author":"RL Buckner","year":"2005","unstructured":"Buckner RL et al (2005) Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25(34):7709\u20137717","journal-title":"J Neurosci"},{"issue":"6","key":"810_CR12","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1002\/bies.201500004","volume":"37","author":"MA Busche","year":"2015","unstructured":"Busche MA, Konnerth A (2015) Neuronal hyperactivity--a key defect in Alzheimer's disease? Bioessays 37(6):624\u2013632","journal-title":"Bioessays"},{"issue":"22","key":"810_CR13","doi-asserted-by":"publisher","first-page":"8740","DOI":"10.1073\/pnas.1206171109","volume":"109","author":"MA Busche","year":"2012","unstructured":"Busche MA et al (2012) Critical role of soluble amyloid-beta for early hippocampal hyperactivity in a mouse model of Alzheimer\u2019s disease. Proc Natl Acad Sci U S A 109(22):8740\u20138745","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"810_CR14","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1038\/nn.4137","volume":"18","author":"MA Busche","year":"2015","unstructured":"Busche MA et al (2015) Rescue of long-range circuit dysfunction in Alzheimer's disease models. Nat Neurosci 18(11):1623\u20131630","journal-title":"Nat Neurosci"},{"issue":"7","key":"810_CR15","first-page":"1326","volume":"22","author":"D Cordes","year":"2001","unstructured":"Cordes D et al (2001) Frequencies contributing to functional connectivity in the cerebral cortex in \u201cresting-state\u201d data. AJNR Am J Neuroradiol 22(7):1326\u20131333","journal-title":"AJNR Am J Neuroradiol"},{"issue":"4","key":"810_CR16","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/j.cell.2015.12.056","volume":"164","author":"B De Strooper","year":"2016","unstructured":"De Strooper B, Karran E (2016) The cellular phase of Alzheimer\u2019s disease. Cell 164(4):603\u2013615","journal-title":"Cell"},{"issue":"2","key":"810_CR17","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1007\/s00401-016-1662-x","volume":"133","author":"E Drummond","year":"2017","unstructured":"Drummond E, Wisniewski T (2017) Alzheimer\u2019s disease: experimental models and reality. Acta Neuropathol 133(2):155\u2013175","journal-title":"Acta Neuropathol"},{"key":"810_CR18","doi-asserted-by":"publisher","unstructured":"Fazlollahi A et al (2019) Increased cerebral blood flow with increased amyloid burden in the preclinical phase of alzheimer\u2019s disease. J Magn Reson Imaging. https:\/\/doi.org\/10.1002\/jmri.26810","DOI":"10.1002\/jmri.26810"},{"issue":"17","key":"810_CR19","doi-asserted-by":"publisher","first-page":"7209","DOI":"10.1073\/pnas.0811879106","volume":"106","author":"N Filippini","year":"2009","unstructured":"Filippini N et al (2009) Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A 106(17):7209\u20137214","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"Pt 2","key":"810_CR20","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1016\/j.neuroimage.2014.08.043","volume":"102","author":"J Grandjean","year":"2014","unstructured":"Grandjean J et al (2014) Optimization of anesthesia protocol for resting-state fMRI in mice based on differential effects of anesthetics on functional connectivity patterns. Neuroimage 102(Pt 2):838\u2013847","journal-title":"Neuroimage"},{"key":"810_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neuroimage.2016.03.042","volume":"134","author":"J Grandjean","year":"2016","unstructured":"Grandjean J et al (2016) Complex interplay between brain function and structure during cerebral amyloidosis in APP transgenic mouse strains revealed by multi-parametric MRI comparison. Neuroimage 134:1\u201311","journal-title":"Neuroimage"},{"issue":"1","key":"810_CR22","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1073\/pnas.0135058100","volume":"100","author":"MD Greicius","year":"2003","unstructured":"Greicius MD et al (2003) Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci U S A 100(1):253\u2013258","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"13","key":"810_CR23","doi-asserted-by":"publisher","first-page":"4637","DOI":"10.1073\/pnas.0308627101","volume":"101","author":"MD Greicius","year":"2004","unstructured":"Greicius MD et al (2004) Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A 101(13):4637\u20134642","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"810_CR24","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.bbadis.2011.07.008","volume":"1822","author":"A Hafkemeijer","year":"2012","unstructured":"Hafkemeijer A, van der Grond J, Rombouts SA (2012) Imaging the default mode network in aging and dementia. Biochim Biophys Acta 1822(3):431\u2013441","journal-title":"Biochim Biophys Acta"},{"key":"810_CR25","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.neuroimage.2015.10.009","volume":"125","author":"L Hammelrath","year":"2016","unstructured":"Hammelrath L et al (2016) Morphological maturation of the mouse brain: an in vivo MRI and histology investigation. Neuroimage 125:144\u2013152","journal-title":"Neuroimage"},{"issue":"19","key":"810_CR26","doi-asserted-by":"publisher","first-page":"1778","DOI":"10.1212\/WNL.0b013e31828726f5","volume":"80","author":"LE Hebert","year":"2013","unstructured":"Hebert LE et al (2013) Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 80(19):1778\u20131783","journal-title":"Neurology"},{"issue":"13","key":"810_CR27","doi-asserted-by":"publisher","first-page":"5161","DOI":"10.1073\/pnas.0600948103","volume":"103","author":"JS Jacobsen","year":"2006","unstructured":"Jacobsen JS et al (2006) Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer\u2019s disease. Proc Natl Acad Sci U S A 103(13):5161\u20135166","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"810_CR28","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/s13024-017-0231-7","volume":"12","author":"JL Jankowsky","year":"2017","unstructured":"Jankowsky JL, Zheng H (2017) Practical considerations for choosing a mouse model of Alzheimer\u2019s disease. Mol Neurodegener 12(1):89","journal-title":"Mol Neurodegener"},{"issue":"12","key":"810_CR29","doi-asserted-by":"publisher","first-page":"e355","DOI":"10.1371\/journal.pmed.0020355","volume":"2","author":"JL Jankowsky","year":"2005","unstructured":"Jankowsky JL et al (2005) Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med 2(12):e355","journal-title":"PLoS Med"},{"key":"810_CR30","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3389\/fnins.2018.00025","volume":"12","author":"F Kametani","year":"2018","unstructured":"Kametani F, Hasegawa M (2018) Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer\u2019s disease. Front Neurosci 12:25","journal-title":"Front Neurosci"},{"issue":"9","key":"810_CR31","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/nrd3505","volume":"10","author":"E Karran","year":"2011","unstructured":"Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698\u2013712","journal-title":"Nat Rev Drug Discov"},{"issue":"11","key":"810_CR32","doi-asserted-by":"publisher","first-page":"a006320","DOI":"10.1101\/cshperspect.a006320","volume":"2","author":"FM LaFerla","year":"2012","unstructured":"LaFerla FM, Green KN (2012) Animal models of Alzheimer disease. Cold Spring Harb Perspect Med 2(11):a006320","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"1\u20132","key":"810_CR33","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/S0006-8993(99)01698-4","volume":"840","author":"J Larson","year":"1999","unstructured":"Larson J et al (1999) Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice. Brain Res 840(1\u20132):23\u201335","journal-title":"Brain Res"},{"issue":"4","key":"810_CR34","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1038\/s41591-019-0375-9","volume":"25","author":"EP Moreno-Jimenez","year":"2019","unstructured":"Moreno-Jimenez EP et al (2019) Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer\u2019s disease. Nat Med 25(4):554\u2013560","journal-title":"Nat Med"},{"issue":"7","key":"810_CR35","doi-asserted-by":"publisher","first-page":"a006338","DOI":"10.1101\/cshperspect.a006338","volume":"2","author":"L Mucke","year":"2012","unstructured":"Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2(7):a006338","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"5","key":"810_CR36","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1038\/nrn.2017.29","volume":"18","author":"UC Muller","year":"2017","unstructured":"Muller UC, Deller T, Korte M (2017) Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 18(5):281\u2013298","journal-title":"Nat Rev Neurosci"},{"issue":"7","key":"810_CR37","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1021\/cn500105p","volume":"5","author":"P Nilsson","year":"2014","unstructured":"Nilsson P, Saito T, Saido TC (2014) New mouse model of Alzheimer\u2019s. ACS Chem Neurosci 5(7):499\u2013502","journal-title":"ACS Chem Neurosci"},{"key":"810_CR38","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1146\/annurev-neuro-061010-113613","volume":"34","author":"RJ O\u2019Brien","year":"2011","unstructured":"O\u2019Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer\u2019s disease. Annu Rev Neurosci 34:185\u2013204","journal-title":"Annu Rev Neurosci"},{"issue":"Pt 1","key":"810_CR39","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1113\/jphysiol.2006.111203","volume":"575","author":"HA Pearson","year":"2006","unstructured":"Pearson HA, Peers C (2006) Physiological roles for amyloid beta peptides. J Physiol 575(Pt 1):5\u201310","journal-title":"J Physiol"},{"issue":"4","key":"810_CR40","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1056\/NEJMra0909142","volume":"362","author":"HW Querfurth","year":"2010","unstructured":"Querfurth HW, LaFerla FM (2010) Alzheimer\u2019s disease. N Engl J Med 362(4):329\u2013344","journal-title":"N Engl J Med"},{"issue":"6","key":"810_CR41","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1002\/ana.22105","volume":"68","author":"YT Quiroz","year":"2010","unstructured":"Quiroz YT et al (2010) Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease. Ann Neurol 68(6):865\u2013875","journal-title":"Ann Neurol"},{"issue":"8","key":"810_CR42","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1001\/jamaneurol.2015.1099","volume":"72","author":"YT Quiroz","year":"2015","unstructured":"Quiroz YT et al (2015) Brain imaging and blood biomarker abnormalities in children with autosomal dominant Alzheimer disease: a cross-sectional study. JAMA Neurol 72(8):912\u2013919","journal-title":"JAMA Neurol"},{"key":"810_CR43","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1750-1326-7-28","volume":"7","author":"SP Rodgers","year":"2012","unstructured":"Rodgers SP et al (2012) Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult. Mol Neurodegener 7:28","journal-title":"Mol Neurodegener"},{"issue":"12","key":"810_CR44","doi-asserted-by":"publisher","first-page":"e84241","DOI":"10.1371\/journal.pone.0084241","volume":"8","author":"D Shah","year":"2013","unstructured":"Shah D et al (2013) Resting state FMRI reveals diminished functional connectivity in a mouse model of amyloidosis. PLoS One 8(12):e84241","journal-title":"PLoS One"},{"issue":"9","key":"810_CR45","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1016\/j.jalz.2016.03.010","volume":"12","author":"D Shah","year":"2016","unstructured":"Shah D et al (2016) Early pathologic amyloid induces hypersynchrony of BOLD resting-state networks in transgenic mice and provides an early therapeutic window before amyloid plaque deposition. Alzheimers Dement 12(9):964\u2013976","journal-title":"Alzheimers Dement"},{"issue":"1","key":"810_CR46","doi-asserted-by":"publisher","first-page":"6264","DOI":"10.1038\/s41598-018-24657-9","volume":"8","author":"D Shah","year":"2018","unstructured":"Shah D et al (2018) Spatial reversal learning defect coincides with hypersynchronous telencephalic BOLD functional connectivity in APP (NL-F\/NL-F) knock-in mice. Sci Rep 8(1):6264","journal-title":"Sci Rep"},{"issue":"5","key":"810_CR47","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.biopsych.2012.11.028","volume":"74","author":"YI Sheline","year":"2013","unstructured":"Sheline YI, Raichle ME (2013) Resting state functional connectivity in preclinical Alzheimer\u2019s disease. Biol Psychiatry 74(5):340\u2013347","journal-title":"Biol Psychiatry"},{"key":"810_CR48","doi-asserted-by":"publisher","first-page":"16322","DOI":"10.1038\/srep16322","volume":"5","author":"JP Shine","year":"2015","unstructured":"Shine JP et al (2015) APOE-epsilon4 selectively modulates posteromedial cortex activity during scene perception and short-term memory in young healthy adults. Sci Rep 5:16322","journal-title":"Sci Rep"},{"issue":"3","key":"810_CR49","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.nbd.2008.11.005","volume":"33","author":"AM Simon","year":"2009","unstructured":"Simon AM et al (2009) Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Abeta levels. Neurobiol Dis 33(3):369\u2013378","journal-title":"Neurobiol Dis"},{"key":"810_CR50","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.neurobiolaging.2018.05.023","volume":"69","author":"N Sinha","year":"2018","unstructured":"Sinha N et al (2018) APOE epsilon4 status in healthy older African Americans is associated with deficits in pattern separation and hippocampal hyperactivation. Neurobiol Aging 69:221\u2013229","journal-title":"Neurobiol Aging"},{"issue":"1","key":"810_CR51","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s40478-019-0670-1","volume":"7","author":"S Sri","year":"2019","unstructured":"Sri S et al (2019) Emergence of synaptic and cognitive impairment in a mature-onset APP mouse model of Alzheimer\u2019s disease. Acta Neuropathol Commun 7(1):25","journal-title":"Acta Neuropathol Commun"},{"issue":"4","key":"810_CR52","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/s41593-018-0080-x","volume":"21","author":"B Styr","year":"2018","unstructured":"Styr B, Slutsky I (2018) Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer\u2019s disease. Nat Neurosci 21(4):463\u2013473","journal-title":"Nat Neurosci"},{"issue":"6","key":"810_CR53","doi-asserted-by":"publisher","first-page":"550","DOI":"10.3390\/cells8060550","volume":"8","author":"BL Tang","year":"2019","unstructured":"Tang BL (2019) Amyloid Precursor Protein (APP) and GABAergic Neurotransmission. Cells 8(6):550","journal-title":"Cells"},{"issue":"25","key":"810_CR54","doi-asserted-by":"publisher","first-page":"6771","DOI":"10.1523\/JNEUROSCI.5564-06.2007","volume":"27","author":"L Verret","year":"2007","unstructured":"Verret L et al (2007) Alzheimer\u2019s-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J Neurosci 27(25):6771\u20136780","journal-title":"J Neurosci"},{"issue":"8","key":"810_CR55","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.tics.2017.05.008","volume":"21","author":"JL Voss","year":"2017","unstructured":"Voss JL et al (2017) A closer look at the Hippocampus and memory. Trends Cogn Sci 21(8):577\u2013588","journal-title":"Trends Cogn Sci"},{"issue":"11","key":"810_CR56","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1002\/hbm.21153","volume":"32","author":"X Wu","year":"2011","unstructured":"Wu X et al (2011) Altered default mode network connectivity in Alzheimer\u2019s disease--a resting functional MRI and Bayesian network study. Hum Brain Mapp 32(11):1868\u20131881","journal-title":"Hum Brain Mapp"},{"issue":"34","key":"810_CR57","doi-asserted-by":"publisher","first-page":"10706","DOI":"10.1523\/JNEUROSCI.2637-09.2009","volume":"29","author":"P Yan","year":"2009","unstructured":"Yan P et al (2009) Characterizing the appearance and growth of amyloid plaques in APP\/PS1 mice. J Neurosci 29(34):10706\u201310714","journal-title":"J Neurosci"},{"issue":"4","key":"810_CR58","doi-asserted-by":"publisher","first-page":"280","DOI":"10.4161\/cam.5.4.16986","volume":"5","author":"ZD Zhou","year":"2011","unstructured":"Zhou ZD et al (2011) The roles of amyloid precursor protein (APP) in neurogenesis: implications to pathogenesis and therapy of Alzheimer disease. Cell Adhes Migr 5(4):280\u2013292","journal-title":"Cell Adhes Migr"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-019-0810-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s40478-019-0810-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-019-0810-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T19:36:54Z","timestamp":1605209814000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-019-0810-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,14]]},"references-count":58,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["810"],"URL":"https:\/\/doi.org\/10.1186\/s40478-019-0810-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/723981","asserted-by":"object"}]},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,14]]},"assertion":[{"value":"9 August 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All procedures were performed in strict accordance with the European Directive 2010\/63\/EU on the protection of animals used for scientific purposes. The protocols were approved by the Committee on Animal Care and Use at the University of Antwerp, Belgium (permit number 2014\u201376). All animals were housed in a room in constant temperature (22\u2009\u00b1\u20092\u2009\u00b0C) and humidity (55\u2009\u00b1\u200910%), with a 12\u2009h light\/dark cycle (light on at 07:00\u2009AM) and free access to food and water available ad libitum. All efforts were made to ensure animal welfare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"180"}}