{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:10:26Z","timestamp":1770815426988,"version":"3.50.1"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"name":"Santa Casa Mantero Belard Award 2015","award":["MB-1049-2015"],"award-info":[{"award-number":["MB-1049-2015"]}]},{"name":"Foundation for Science and Technology","award":["PEst UID\/NEU\/04539\/2013 and UID\/NEU\/04539\/2019: CNC.IBILI; PEst UIDB\/04539\/2020 and UIDP\/04539\/2020: CIBB"],"award-info":[{"award-number":["PEst UID\/NEU\/04539\/2013 and UID\/NEU\/04539\/2019: CNC.IBILI; PEst UIDB\/04539\/2020 and UIDP\/04539\/2020: CIBB"]}]},{"name":"COMPETE-FEDER","award":["POCI-01-0145-FEDER-007440"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007440"]}]},{"name":"Centro 2020 Regional Operational Programme","award":["CENTRO-01-0145-FEDER-000008: BrainHealth 2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008: BrainHealth 2020"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2021,7]]},"DOI":"10.1007\/s12035-021-02316-x","type":"journal-article","created":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T20:46:05Z","timestamp":1613767565000},"page":"3043-3060","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Retina and Brain Display Early and Differential Molecular and Cellular Changes in the 3xTg-AD Mouse Model of Alzheimer\u2019s Disease"],"prefix":"10.1007","volume":"58","author":[{"given":"Ana Catarina","family":"Rodrigues-Neves","sequence":"first","affiliation":[]},{"given":"Rafael","family":"Carecho","sequence":"additional","affiliation":[]},{"given":"S\u00f3nia Catarina","family":"Correia","sequence":"additional","affiliation":[]},{"given":"Cristina","family":"Carvalho","sequence":"additional","affiliation":[]},{"given":"Elisa Juli\u00e3o","family":"Campos","sequence":"additional","affiliation":[]},{"given":"Filipa Isabel","family":"Baptista","sequence":"additional","affiliation":[]},{"given":"Paula Isabel","family":"Moreira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0477-1641","authenticated-orcid":false,"given":"Ant\u00f3nio Francisco","family":"Ambr\u00f3sio","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"issue":"1","key":"2316_CR1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nrneurol.2012.227","volume":"9","author":"A London","year":"2013","unstructured":"London A, Benhar I, Schwartz M (2013) The retina as a window to the brain\u2014from eye research to CNS disorders. Nat Rev Neurol 9(1):44\u201353. https:\/\/doi.org\/10.1038\/nrneurol.2012.227","journal-title":"Nat Rev Neurol"},{"issue":"2","key":"2316_CR2","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.jalz.2013.06.004","volume":"10","author":"LY Chang","year":"2014","unstructured":"Chang LY, Lowe J, Ardiles A, Lim J, Grey AC, Robertson K, Danesh-Meyer H, Palacios AG et al (2014) Alzheimer\u2019s disease in the human eye. Clinical tests that identify ocular and visual information processing deficit as biomarkers. Alzheimers Dement 10(2):251\u2013261. https:\/\/doi.org\/10.1016\/j.jalz.2013.06.004","journal-title":"Alzheimers Dement"},{"key":"2316_CR3","doi-asserted-by":"publisher","first-page":"5416","DOI":"10.1007\/s12035-018-1461-6","volume":"56","author":"S Chiquita","year":"2019","unstructured":"Chiquita S, Rodrigues-Neves AC, Baptista FI, Carecho R, Moreira PI, Castelo-Branco M, Ambrosio AF (2019) The retina as a window or mirror of the brain changes detected in Alzheimer\u2019s disease: critical aspects to unravel. Mol Neurobiol. 56:5416\u20135435. https:\/\/doi.org\/10.1007\/s12035-018-1461-6","journal-title":"Mol Neurobiol."},{"issue":"2","key":"2316_CR4","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1097\/00005072-199403000-00006","volume":"53","author":"SC Liew","year":"1994","unstructured":"Liew SC, Penfold PL, Provis JM, Madigan MC, Billson FA (1994) Modulation of MHC class II expression in the absence of lymphocytic infiltrates in Alzheimer\u2019s retinae. J Neuropathol Exp Neurol 53(2):150\u2013157. https:\/\/doi.org\/10.1097\/00005072-199403000-00006","journal-title":"J Neuropathol Exp Neurol"},{"issue":"3","key":"2316_CR5","first-page":"385","volume":"17","author":"JC Blanks","year":"1996","unstructured":"Blanks JC, Schmidt SY, Torigoe Y, Porrello KV, Hinton DR, Blanks RH (1996) Retinal pathology in Alzheimer\u2019s disease. II. Regional neuron loss and glial changes in GCL. Neurobiol Aging 17(3):385\u2013395","journal-title":"II. Regional neuron loss and glial changes in GCL. Neurobiol Aging"},{"issue":"2","key":"2316_CR6","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/mp.2017.246","volume":"23","author":"KE Hopperton","year":"2018","unstructured":"Hopperton KE, Mohammad D, Trepanier MO, Giuliano V, Bazinet RP (2018) Markers of microglia in post-mortem brain samples from patients with Alzheimer\u2019s disease: a systematic review. Mol Psychiatry 23(2):177\u2013198. https:\/\/doi.org\/10.1038\/mp.2017.246","journal-title":"Mol Psychiatry"},{"issue":"8","key":"2316_CR7","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1056\/NEJM198608213150804","volume":"315","author":"DR Hinton","year":"1986","unstructured":"Hinton DR, Sadun AA, Blanks JC, Miller CA (1986) Optic-nerve degeneration in Alzheimer\u2019s disease. N Engl J Med 315(8):485\u2013487. https:\/\/doi.org\/10.1056\/NEJM198608213150804","journal-title":"N Engl J Med"},{"key":"2316_CR8","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1111\/j.1749-6632.1991.tb00188.x","volume":"640","author":"JC Blanks","year":"1991","unstructured":"Blanks JC, Torigoe Y, Hinton DR, Blanks RH (1991) Retinal degeneration in the macula of patients with Alzheimer\u2019s disease. Ann N Y Acad Sci 640:44\u201346. https:\/\/doi.org\/10.1111\/j.1749-6632.1991.tb00188.x","journal-title":"Ann N Y Acad Sci"},{"issue":"3","key":"2316_CR9","first-page":"377","volume":"17","author":"JC Blanks","year":"1996","unstructured":"Blanks JC, Torigoe Y, Hinton DR, Blanks RH (1996) Retinal pathology in Alzheimer\u2019s disease. I. Ganglion cell loss in foveal\/parafoveal retina. Neurobiol Aging 17(3):377\u2013384","journal-title":"I. Ganglion cell loss in foveal\/parafoveal retina. Neurobiol Aging"},{"issue":"1","key":"2316_CR10","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1002\/ana.24548","volume":"79","author":"C La Morgia","year":"2016","unstructured":"La Morgia C, Ross-Cisneros FN, Koronyo Y, Hannibal J, Gallassi R, Cantalupo G, Sambati L, Pan BX et al (2016) Melanopsin retinal ganglion cell loss in Alzheimer disease. Ann Neurol 79(1):90\u2013109. https:\/\/doi.org\/10.1002\/ana.24548","journal-title":"Ann Neurol"},{"issue":"2","key":"2316_CR11","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/0006-8993(89)90653-7","volume":"501","author":"JC Blanks","year":"1989","unstructured":"Blanks JC, Hinton DR, Sadun AA, Miller CA (1989) Retinal ganglion cell degeneration in Alzheimer\u2019s disease. Brain Res 501(2):364\u2013372. https:\/\/doi.org\/10.1016\/0006-8993(89)90653-7","journal-title":"Brain Res"},{"issue":"Suppl 1","key":"2316_CR12","doi-asserted-by":"publisher","first-page":"S204","DOI":"10.1016\/j.neuroimage.2010.06.020","volume":"54","author":"M Koronyo-Hamaoui","year":"2011","unstructured":"Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller CA, Ko MK, Black KL, Schwartz M, Farkas DL (2011) Identification of amyloid plaques in retinas from Alzheimer\u2019s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage 54(Suppl 1):S204\u2013S217. https:\/\/doi.org\/10.1016\/j.neuroimage.2010.06.020","journal-title":"Neuroimage"},{"issue":"1","key":"2316_CR13","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/bpa.12070","volume":"24","author":"CY Ho","year":"2014","unstructured":"Ho CY, Troncoso JC, Knox D, Stark W, Eberhart CG (2014) Beta-amyloid, phospho-tau and alpha-synuclein deposits similar to those in the brain are not identified in the eyes of Alzheimer\u2019s and Parkinson\u2019s disease patients. Brain Pathol 24(1):25\u201332. https:\/\/doi.org\/10.1111\/bpa.12070","journal-title":"Brain Pathol"},{"key":"2316_CR14","doi-asserted-by":"publisher","unstructured":"Koronyo Y, Biggs D, Barron E, Boyer DS, Pearlman JA, Au WJ, Kile SJ, Blanco A et al (2017) Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer\u2019s disease. JCI Insight 2(16). https:\/\/doi.org\/10.1172\/jci.insight.93621","DOI":"10.1172\/jci.insight.93621"},{"issue":"13","key":"2316_CR15","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1093\/hmg\/ddz045","volume":"28","author":"S Chiquita","year":"2019","unstructured":"Chiquita S, Ribeiro M, Castelhano J, Oliveira F, Sereno J, Batista M, Abrunhosa A, Rodrigues-Neves AC et al (2019) A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss. Hum Mol Genet 28(13):2174\u20132188. https:\/\/doi.org\/10.1093\/hmg\/ddz045","journal-title":"Hum Mol Genet"},{"issue":"1","key":"2316_CR16","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1186\/s13195-019-0542-8","volume":"11","author":"S Chiquita","year":"2019","unstructured":"Chiquita S, Campos EJ, Castelhano J, Ribeiro M, Sereno J, Moreira PI, Castelo-Branco M, Ambrosio AF (2019) Retinal thinning of inner sub-layers is associated with cortical atrophy in a mouse model of Alzheimer\u2019s disease: a longitudinal multimodal in vivo study. Alzheimers Res Ther 11(1):90. https:\/\/doi.org\/10.1186\/s13195-019-0542-8","journal-title":"Alzheimers Res Ther"},{"issue":"3","key":"2316_CR17","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/S0896-6273(03)00434-3","volume":"39","author":"S Oddo","year":"2003","unstructured":"Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP et al (2003) Triple-transgenic model of Alzheimer\u2019s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409\u2013421","journal-title":"Neuron"},{"key":"2316_CR18","doi-asserted-by":"crossref","unstructured":"Casali BT, Landreth GE (2016) Abeta extraction from murine brain homogenates. Bio Protoc 6 (8). doi:10.21769\/BioProtoc.1787","DOI":"10.21769\/BioProtoc.1787"},{"issue":"6","key":"2316_CR19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0065515","volume":"8","author":"FI Baptista","year":"2013","unstructured":"Baptista FI, Pinto MJ, Elvas F, Almeida RD, Ambrosio AF (2013) Diabetes alters KIF1A and KIF5B motor proteins in the hippocampus. PLoS One 8(6):e65515. https:\/\/doi.org\/10.1371\/journal.pone.0065515","journal-title":"PLoS One"},{"key":"2316_CR20","unstructured":"George Paxinos KF (2008). The mouse brain in stereotaxic coordinates, compact. 3rd Edition. Elsevier Academic Press:256"},{"issue":"7","key":"2316_CR21","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1038\/mp.2016.173","volume":"22","author":"L Caetano","year":"2017","unstructured":"Caetano L, Pinheiro H, Patricio P, Mateus-Pinheiro A, Alves ND, Coimbra B, Baptista FI, Henriques SN et al (2017) Adenosine A2A receptor regulation of microglia morphological remodeling-gender bias in physiology and in a model of chronic anxiety. Mol Psychiatry 22(7):1035\u20131043. https:\/\/doi.org\/10.1038\/mp.2016.173","journal-title":"Mol Psychiatry"},{"issue":"6","key":"2316_CR22","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1111\/ejn.14561","volume":"51","author":"C Simoes-Henriques","year":"2020","unstructured":"Simoes-Henriques C, Mateus-Pinheiro M, Gaspar R, Pinheiro H, Mendes Duarte J, Baptista FI, Canas PM, Fontes-Ribeiro CA et al (2020) Microglia cytoarchitecture in the brain of adenosine A2A receptor knockout mice: brain region and sex specificities. Eur J Neurosci 51(6):1377\u20131387. https:\/\/doi.org\/10.1111\/ejn.14561","journal-title":"Eur J Neurosci"},{"issue":"1","key":"2316_CR23","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1002\/glia.23476","volume":"67","author":"JM Duarte","year":"2019","unstructured":"Duarte JM, Gaspar R, Caetano L, Patricio P, Soares-Cunha C, Mateus-Pinheiro A, Alves ND, Santos AR et al (2019) Region-specific control of microglia by adenosine A2A receptors: uncoupling anxiety and associated cognitive deficits in female rats. Glia 67(1):182\u2013192. https:\/\/doi.org\/10.1002\/glia.23476","journal-title":"Glia"},{"key":"2316_CR24","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/1471-2202-9-81","volume":"9","author":"MA Mastrangelo","year":"2008","unstructured":"Mastrangelo MA, Bowers WJ (2008) Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer\u2019s disease-related pathologies in male triple-transgenic mice. BMC Neurosci 9:81. https:\/\/doi.org\/10.1186\/1471-2202-9-81","journal-title":"BMC Neurosci"},{"issue":"5","key":"2316_CR25","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.2337\/db11-1186","volume":"61","author":"C Carvalho","year":"2012","unstructured":"Carvalho C, Cardoso S, Correia SC, Santos RX, Santos MS, Baldeiras I, Oliveira CR, Moreira PI (2012) Metabolic alterations induced by sucrose intake and Alzheimer\u2019s disease promote similar brain mitochondrial abnormalities. Diabetes 61(5):1234\u20131242. https:\/\/doi.org\/10.2337\/db11-1186","journal-title":"Diabetes"},{"issue":"3","key":"2316_CR26","doi-asserted-by":"publisher","first-page":"623","DOI":"10.3233\/JAD-130005","volume":"35","author":"C Carvalho","year":"2013","unstructured":"Carvalho C, Machado N, Mota PC, Correia SC, Cardoso S, Santos RX, Santos MS, Oliveira CR et al (2013) Type 2 diabetic and Alzheimer\u2019s disease mice present similar behavioral, cognitive, and vascular anomalies. J Alzheimers Dis 35(3):623\u2013635. https:\/\/doi.org\/10.3233\/JAD-130005","journal-title":"J Alzheimers Dis"},{"issue":"8","key":"2316_CR27","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.1016\/j.bbadis.2015.05.001","volume":"1852","author":"C Carvalho","year":"2015","unstructured":"Carvalho C, Santos MS, Oliveira CR, Moreira PI (2015) Alzheimer\u2019s disease and type 2 diabetes-related alterations in brain mitochondria, autophagy and synaptic markers. Biochim Biophys Acta 1852(8):1665\u20131675. https:\/\/doi.org\/10.1016\/j.bbadis.2015.05.001","journal-title":"Biochim Biophys Acta"},{"issue":"3","key":"2316_CR28","doi-asserted-by":"publisher","first-page":"245","DOI":"10.4062\/biomolther.2012.20.3.245","volume":"20","author":"SS Yoon","year":"2012","unstructured":"Yoon SS, Jo SA (2012) Mechanisms of amyloid-beta peptide clearance: potential therapeutic targets for Alzheimer\u2019s disease. Biomol Ther (Seoul) 20(3):245\u2013255. https:\/\/doi.org\/10.4062\/biomolther.2012.20.3.245","journal-title":"Biomol Ther (Seoul)"},{"key":"2316_CR29","doi-asserted-by":"publisher","first-page":"136","DOI":"10.3389\/fnagi.2015.00136","volume":"7","author":"A Ramanathan","year":"2015","unstructured":"Ramanathan A, Nelson AR, Sagare AP, Zlokovic BV (2015) Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer\u2019s disease: the role, regulation and restoration of LRP1. Front Aging Neurosci 7:136. https:\/\/doi.org\/10.3389\/fnagi.2015.00136","journal-title":"Front Aging Neurosci"},{"issue":"4","key":"2316_CR30","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/alzrt187","volume":"5","author":"KR Wildsmith","year":"2013","unstructured":"Wildsmith KR, Holley M, Savage JC, Skerrett R, Landreth GE (2013) Evidence for impaired amyloid beta clearance in Alzheimer\u2019s disease. Alzheimers Res Ther 5(4):33. https:\/\/doi.org\/10.1186\/alzrt187","journal-title":"Alzheimers Res Ther"},{"issue":"6","key":"2316_CR31","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/s41419-018-0740-5","volume":"9","author":"A Grimaldi","year":"2018","unstructured":"Grimaldi A, Brighi C, Peruzzi G, Ragozzino D, Bonanni V, Limatola C, Ruocco G, Di Angelantonio S (2018) Inflammation, neurodegeneration and protein aggregation in the retina as ocular biomarkers for Alzheimer\u2019s disease in the 3xTg-AD mouse model. Cell Death Dis 9(6):685. https:\/\/doi.org\/10.1038\/s41419-018-0740-5","journal-title":"Cell Death Dis"},{"issue":"12","key":"2316_CR32","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1097\/WNR.0b013e3283497334","volume":"22","author":"PN Alexandrov","year":"2011","unstructured":"Alexandrov PN, Pogue A, Bhattacharjee S, Lukiw WJ (2011) Retinal amyloid peptides and complement factor H in transgenic models of Alzheimer\u2019s disease. Neuroreport 22(12):623\u2013627. https:\/\/doi.org\/10.1097\/WNR.0b013e3283497334","journal-title":"Neuroreport"},{"issue":"7","key":"2316_CR33","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1007\/BF00964629","volume":"10","author":"TJ Sprinkle","year":"1985","unstructured":"Sprinkle TJ, McMorris FA, Yoshino J, DeVries GH (1985) Differential expression of 2':3'-cyclic nucleotide 3'-phosphodiesterase in cultured central, peripheral, and extraneural cells. Neurochem Res 10(7):919\u2013931. https:\/\/doi.org\/10.1007\/BF00964629","journal-title":"Neurochem Res"},{"issue":"4","key":"2316_CR34","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1111\/j.1471-4159.2007.04607.x","volume":"102","author":"S Oddo","year":"2007","unstructured":"Oddo S, Caccamo A, Cheng D, Jouleh B, Torp R, LaFerla FM (2007) Genetically augmenting tau levels does not modulate the onset or progression of Abeta pathology in transgenic mice. J Neurochem 102(4):1053\u20131063. https:\/\/doi.org\/10.1111\/j.1471-4159.2007.04607.x","journal-title":"J Neurochem"},{"issue":"2","key":"2316_CR35","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1111\/nan.12084","volume":"40","author":"S Mondragon-Rodriguez","year":"2014","unstructured":"Mondragon-Rodriguez S, Perry G, Luna-Munoz J, Acevedo-Aquino MC, Williams S (2014) Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer\u2019s disease and Down syndrome. Neuropathol Appl Neurobiol 40(2):121\u2013135. https:\/\/doi.org\/10.1111\/nan.12084","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"6","key":"2316_CR36","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/sj.mn.7800212","volume":"10","author":"M Ujiie","year":"2003","unstructured":"Ujiie M, Dickstein DL, Carlow DA, Jefferies WA (2003) Blood\u2013brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10(6):463\u2013470. https:\/\/doi.org\/10.1038\/sj.mn.7800212","journal-title":"Microcirculation"},{"issue":"2","key":"2316_CR37","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/S0002-9440(10)62995-1","volume":"167","author":"S Kumar-Singh","year":"2005","unstructured":"Kumar-Singh S, Pirici D, McGowan E, Serneels S, Ceuterick C, Hardy J, Duff K, Dickson D et al (2005) Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer\u2019s disease are centered on vessel walls. Am J Pathol 167(2):527\u2013543. https:\/\/doi.org\/10.1016\/S0002-9440(10)62995-1","journal-title":"Am J Pathol"},{"issue":"2","key":"2316_CR38","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.neuron.2015.09.036","volume":"88","author":"N Bien-Ly","year":"2015","unstructured":"Bien-Ly N, Boswell CA, Jeet S, Beach TG, Hoyte K, Luk W, Shihadeh V, Ulufatu S et al (2015) Lack of widespread BBB disruption in Alzheimer\u2019s disease models: focus on therapeutic antibodies. Neuron 88(2):289\u2013297. https:\/\/doi.org\/10.1016\/j.neuron.2015.09.036","journal-title":"Neuron"},{"issue":"8","key":"2316_CR39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023789","volume":"6","author":"KE Biron","year":"2011","unstructured":"Biron KE, Dickstein DL, Gopaul R, Jefferies WA (2011) Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer\u2019s disease. PLoS One 6(8):e23789. https:\/\/doi.org\/10.1371\/journal.pone.0023789","journal-title":"PLoS One"},{"issue":"9","key":"2316_CR40","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1016\/j.neurobiolaging.2014.03.008","volume":"35","author":"SW Park","year":"2014","unstructured":"Park SW, Kim JH, Mook-Jung I, Kim KW, Park WJ, Park KH, Kim JH (2014) Intracellular amyloid beta alters the tight junction of retinal pigment epithelium in 5XFAD mice. Neurobiol Aging 35(9):2013\u20132020. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2014.03.008","journal-title":"Neurobiol Aging"},{"issue":"3","key":"2316_CR41","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/S0301-0082(02)00079-5","volume":"68","author":"DS Auld","year":"2002","unstructured":"Auld DS, Kornecook TJ, Bastianetto S, Quirion R (2002) Alzheimer\u2019s disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol 68(3):209\u2013245","journal-title":"Prog Neurobiol"},{"issue":"2","key":"2316_CR42","doi-asserted-by":"publisher","first-page":"267","DOI":"10.3233\/JAD-2012-100732","volume":"32","author":"MT Girao da Cruz","year":"2012","unstructured":"Girao da Cruz MT, Jordao J, Dasilva KA, Ayala-Grosso CA, Ypsilanti A, Weng YQ, Laferla FM, McLaurin J et al (2012) Early increases in soluble amyloid-beta levels coincide with cholinergic degeneration in 3xTg-AD mice. J Alzheimers Dis 32(2):267\u2013272. https:\/\/doi.org\/10.3233\/JAD-2012-100732","journal-title":"J Alzheimers Dis"},{"key":"2316_CR43","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.exer.2015.04.013","volume":"135","author":"L Gao","year":"2015","unstructured":"Gao L, Chen X, Tang Y, Zhao J, Li Q, Fan X, Xu H, Yin ZQ (2015) Neuroprotective effect of memantine on the retinal ganglion cells of APPswe\/PS1DeltaE9 mice and its immunomodulatory mechanisms. Exp Eye Res 135:47\u201358. https:\/\/doi.org\/10.1016\/j.exer.2015.04.013","journal-title":"Exp Eye Res"},{"issue":"1","key":"2316_CR44","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1111\/j.1460-9568.2005.04549.x","volume":"23","author":"NI Bravarenko","year":"2006","unstructured":"Bravarenko NI, Onufriev MV, Stepanichev MY, Ierusalimsky VN, Balaban PM, Gulyaeva NV (2006) Caspase-like activity is essential for long-term synaptic plasticity in the terrestrial snail Helix. Eur J Neurosci 23(1):129\u2013140. https:\/\/doi.org\/10.1111\/j.1460-9568.2005.04549.x","journal-title":"Eur J Neurosci"},{"issue":"5","key":"2316_CR45","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1016\/j.cell.2010.03.053","volume":"141","author":"Z Li","year":"2010","unstructured":"Li Z, Jo J, Jia JM, Lo SC, Whitcomb DJ, Jiao S, Cho K, Sheng M (2010) Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141(5):859\u2013871. https:\/\/doi.org\/10.1016\/j.cell.2010.03.053","journal-title":"Cell"},{"issue":"1","key":"2316_CR46","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/nn.2709","volume":"14","author":"M D'Amelio","year":"2011","unstructured":"D'Amelio M, Cavallucci V, Middei S, Marchetti C, Pacioni S, Ferri A, Diamantini A, De Zio D et al (2011) Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer\u2019s disease. Nat Neurosci 14(1):69\u201376. https:\/\/doi.org\/10.1038\/nn.2709","journal-title":"Nat Neurosci"},{"key":"2316_CR47","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.neuropharm.2014.01.037","volume":"81","author":"S Revilla","year":"2014","unstructured":"Revilla S, Sunol C, Garcia-Mesa Y, Gimenez-Llort L, Sanfeliu C, Cristofol R (2014) Physical exercise improves synaptic dysfunction and recovers the loss of survival factors in 3xTg-AD mouse brain. Neuropharmacology 81:55\u201363. https:\/\/doi.org\/10.1016\/j.neuropharm.2014.01.037","journal-title":"Neuropharmacology"},{"key":"2316_CR48","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.neuropharm.2017.08.037","volume":"126","author":"DS Sun","year":"2017","unstructured":"Sun DS, Gao LF, Jin L, Wu H, Wang Q, Zhou Y, Fan S, Jiang X et al (2017) Fluoxetine administration during adolescence attenuates cognitive and synaptic deficits in adult 3xTgAD mice. Neuropharmacology 126:200\u2013212. https:\/\/doi.org\/10.1016\/j.neuropharm.2017.08.037","journal-title":"Neuropharmacology"},{"key":"2316_CR49","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.expneurol.2014.06.004","volume":"261","author":"Y Chen","year":"2014","unstructured":"Chen Y, Zhao Y, Dai CL, Liang Z, Run X, Iqbal K, Liu F, Gong CX (2014) Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Abeta level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol 261:610\u2013619. https:\/\/doi.org\/10.1016\/j.expneurol.2014.06.004","journal-title":"Exp Neurol"},{"issue":"1","key":"2316_CR50","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.bbrc.2005.02.121","volume":"330","author":"PJ Yao","year":"2005","unstructured":"Yao PJ, Bushlin I, Furukawa K (2005) Preserved synaptic vesicle recycling in hippocampal neurons in a mouse Alzheimer\u2019s disease model. Biochem Biophys Res Commun 330(1):34\u201338. https:\/\/doi.org\/10.1016\/j.bbrc.2005.02.121","journal-title":"Biochem Biophys Res Commun"},{"key":"2316_CR51","doi-asserted-by":"crossref","unstructured":"Baazaoui N, Flory M, Iqbal K (2017) Synaptic compensation as a probable cause of prolonged mild cognitive impairment in Alzheimer\u2019s disease: implications from a transgenic mouse model of the disease. J Alzheimers Dis 56(4):1385\u20131401","DOI":"10.3233\/JAD-160845"},{"issue":"2","key":"2316_CR52","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1016\/s0002-9440(10)64573-7","volume":"157","author":"EB Mukaetova-Ladinska","year":"2000","unstructured":"Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, Gertz HJ, Xuereb JH, Hills R, Brayne C, Huppert FA et al (2000) Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer\u2019s disease. Am J Pathol 157(2):623\u2013636. https:\/\/doi.org\/10.1016\/s0002-9440(10)64573-7","journal-title":"Am J Pathol"},{"issue":"25","key":"2316_CR53","doi-asserted-by":"publisher","first-page":"10071","DOI":"10.1073\/pnas.1204606109","volume":"109","author":"A Limon","year":"2012","unstructured":"Limon A, Reyes-Ruiz JM, Miledi R (2012) Loss of functional GABA(A) receptors in the Alzheimer diseased brain. Proc Natl Acad Sci U S A 109(25):10071\u201310076. https:\/\/doi.org\/10.1073\/pnas.1204606109","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"2316_CR54","doi-asserted-by":"publisher","first-page":"2956","DOI":"10.1073\/pnas.0611513104","volume":"104","author":"A Bernareggi","year":"2007","unstructured":"Bernareggi A, Duenas Z, Reyes-Ruiz JM, Ruzzier F, Miledi R (2007) Properties of glutamate receptors of Alzheimer\u2019s disease brain transplanted to frog oocytes. Proc Natl Acad Sci U S A 104(8):2956\u20132960. https:\/\/doi.org\/10.1073\/pnas.0611513104","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9","key":"2316_CR55","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.1007\/s10072-013-1289-9","volume":"34","author":"MC Gueli","year":"2013","unstructured":"Gueli MC, Taibi G (2013) Alzheimer\u2019s disease: amino acid levels and brain metabolic status. Neurol Sci 34(9):1575\u20131579. https:\/\/doi.org\/10.1007\/s10072-013-1289-9","journal-title":"Neurol Sci"},{"issue":"1","key":"2316_CR56","doi-asserted-by":"publisher","first-page":"30","DOI":"10.2174\/1567205013666160819125757","volume":"14","author":"V Villette","year":"2017","unstructured":"Villette V, Dutar P (2017) GABAergic microcircuits in Alzheimer\u2019s disease models. Curr Alzheimer Res 14(1):30\u201339","journal-title":"Curr Alzheimer Res"},{"issue":"7","key":"2316_CR57","doi-asserted-by":"publisher","first-page":"2698","DOI":"10.1007\/s00330-016-4669-8","volume":"27","author":"D Huang","year":"2017","unstructured":"Huang D, Liu D, Yin J, Qian T, Shrestha S, Ni H (2017) Glutamate\u2013glutamine and GABA in brain of normal aged and patients with cognitive impairment. Eur Radiol 27(7):2698\u20132705. https:\/\/doi.org\/10.1007\/s00330-016-4669-8","journal-title":"Eur Radiol"},{"issue":"6","key":"2316_CR58","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1111\/jnc.14345","volume":"146","author":"B Calvo-Flores Guzman","year":"2018","unstructured":"Calvo-Flores Guzman B, Vinnakota C, Govindpani K, Waldvogel HJ, Faull RLM, Kwakowsky A (2018) The GABAergic system as a therapeutic target for Alzheimer\u2019s disease. J Neurochem 146(6):649\u2013669. https:\/\/doi.org\/10.1111\/jnc.14345","journal-title":"J Neurochem"},{"issue":"3","key":"2316_CR59","doi-asserted-by":"publisher","first-page":"771","DOI":"10.3233\/JAD-142160","volume":"44","author":"KN Hascup","year":"2015","unstructured":"Hascup KN, Hascup ER (2015) Altered neurotransmission prior to cognitive decline in AbetaPP\/PS1 mice, a model of Alzheimer\u2019s disease. J Alzheimers Dis 44(3):771\u2013776. https:\/\/doi.org\/10.3233\/JAD-142160","journal-title":"J Alzheimers Dis"},{"key":"2316_CR60","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.nbd.2018.05.024","volume":"117","author":"AC Silva","year":"2018","unstructured":"Silva AC, Lemos C, Goncalves FQ, Pliassova AV, Machado NJ, Silva HB, Canas PM, Cunha RA et al (2018) Blockade of adenosine A2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer\u2019s disease. Neurobiol Dis 117:72\u201381. https:\/\/doi.org\/10.1016\/j.nbd.2018.05.024","journal-title":"Neurobiol Dis"},{"issue":"8","key":"2316_CR61","doi-asserted-by":"publisher","first-page":"894","DOI":"10.2174\/1567205013666160129095924","volume":"13","author":"D Dzamba","year":"2016","unstructured":"Dzamba D, Harantova L, Butenko O, Anderova M (2016) Glial cells\u2014the key elements of Alzheimer\u2019s disease. Curr Alzheimer Res 13(8):894\u2013911","journal-title":"Curr Alzheimer Res"},{"issue":"2","key":"2316_CR62","doi-asserted-by":"publisher","first-page":"655","DOI":"10.3233\/JAD-160823","volume":"56","author":"G Chidlow","year":"2017","unstructured":"Chidlow G, Wood JP, Manavis J, Finnie J, Casson RJ (2017) Investigations into retinal pathology in the early stages of a mouse model of Alzheimer\u2019s disease. J Alzheimers Dis 56(2):655\u2013675. https:\/\/doi.org\/10.3233\/JAD-160823","journal-title":"J Alzheimers Dis"},{"key":"2316_CR63","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.exer.2014.08.006","volume":"127","author":"MM Edwards","year":"2014","unstructured":"Edwards MM, Rodriguez JJ, Gutierrez-Lanza R, Yates J, Verkhratsky A, Lutty GA (2014) Retinal macroglia changes in a triple transgenic mouse model of Alzheimer\u2019s disease. Exp Eye Res 127:252\u2013260. https:\/\/doi.org\/10.1016\/j.exer.2014.08.006","journal-title":"Exp Eye Res"},{"key":"2316_CR64","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.neurobiolaging.2017.02.004","volume":"53","author":"S Joly","year":"2017","unstructured":"Joly S, Lamoureux S, Pernet V (2017) Nonamyloidogenic processing of amyloid beta precursor protein is associated with retinal function improvement in aging male APPswe\/PS1DeltaE9 mice. Neurobiol Aging 53:181\u2013191. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2017.02.004","journal-title":"Neurobiol Aging"},{"issue":"6","key":"2316_CR65","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1113\/JP272134","volume":"595","author":"TL Tay","year":"2017","unstructured":"Tay TL, Savage JC, Hui CW, Bisht K, Tremblay ME (2017) Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J Physiol 595(6):1929\u20131945. https:\/\/doi.org\/10.1113\/JP272134","journal-title":"J Physiol"},{"key":"2316_CR66","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.neulet.2013.06.036","volume":"552","author":"JJ Rodriguez","year":"2013","unstructured":"Rodriguez JJ, Noristani HN, Hilditch T, Olabarria M, Yeh CY, Witton J, Verkhratsky A (2013) Increased densities of resting and activated microglia in the dentate gyrus follow senile plaque formation in the CA1 subfield of the hippocampus in the triple transgenic model of Alzheimer\u2019s disease. Neurosci Lett 552:129\u2013134. https:\/\/doi.org\/10.1016\/j.neulet.2013.06.036","journal-title":"Neurosci Lett"},{"key":"2316_CR67","doi-asserted-by":"publisher","unstructured":"Salobrar-Garcia E, Rodrigues-Neves AC, Ramirez AI, de Hoz R, Fernandez-Albarral JA, Lopez-Cuenca I, Ramirez JM, Ambrosio AF et al (2020) Microglial activation in the retina of a triple-transgenic Alzheimer\u2019s disease mouse model (3xTg-AD). Int J Mol Sci 21(3). https:\/\/doi.org\/10.3390\/ijms21030816","DOI":"10.3390\/ijms21030816"},{"issue":"6","key":"2316_CR68","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1111\/bpa.12456","volume":"27","author":"DS Davies","year":"2017","unstructured":"Davies DS, Ma J, Jegathees T, Goldsbury C (2017) Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer\u2019s disease. Brain Pathol 27(6):795\u2013808. https:\/\/doi.org\/10.1111\/bpa.12456","journal-title":"Brain Pathol"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-021-02316-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12035-021-02316-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-021-02316-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T14:32:47Z","timestamp":1625495567000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12035-021-02316-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,19]]},"references-count":68,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["2316"],"URL":"https:\/\/doi.org\/10.1007\/s12035-021-02316-x","relation":{},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,19]]},"assertion":[{"value":"25 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experiments using animals were approved by the Animal Welfare (\u00d3rg\u00e3o Respons\u00e1vel pelo Bem-Estar Animal - ORBEA 16\/2015) of the Coimbra Institute for Clinical and Biomedical research (iCBR), Faculty of Medicine, University of Coimbra, and by Dire\u00e7\u00e3o Geral de Alimenta\u00e7\u00e3o e Veterin\u00e1ria (DGAV 0421\/000\/000\/2015) and conducted in accordance with the European Community directive guidelines for the use of animals in laboratory (2010\/63\/EU) transposed to the Portuguese law in 2013 (Decreto-Lei 113\/2013), and in agreement with the Association for Research in Vision and Ophthalmology statement for animal use.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"All authors have reviewed and approved the manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no conflict of interest.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}