{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:44:57Z","timestamp":1762868697900,"version":"build-2065373602"},"reference-count":62,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T00:00:00Z","timestamp":1640908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["GINOP-2.2.1-15-2017-00034"],"award-info":[{"award-number":["GINOP-2.2.1-15-2017-00034"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The medial temporal lobe memory system has long been identified as the brain region showing the first histopathological changes in early Alzheimer\u2019s disease (AD), and the functional decline observed in patients also points to a loss of function in this brain area. Nonetheless, the exact identity of the neurons and networks that undergo deterioration has not been determined so far. A recent study has identified the entorhinal and hippocampal neural circuits responsible for encoding new episodic memories. Using this novel model we describe the elements of the episodic memory network that are especially vulnerable in early AD. We provide a hypothesis of how reduced reelin signaling within such a network can promote AD-related changes. Establishing novel associations and creating a temporal structure for new episodic memories are both affected in AD. Here, we furnish a reasonable explanation for both of these previous observations.<\/jats:p>","DOI":"10.3390\/ijms23010462","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T01:15:26Z","timestamp":1641518126000},"page":"462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"23","author":[{"given":"Kriszti\u00e1n A.","family":"Kov\u00e1cs","sequence":"first","affiliation":[{"name":"Retina Research Laboratory, Institute of Translational Medicine, Semmelweis University, T\u0171zolt\u00f3 U. 37-47, 1094 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1038\/s41467-020-15701-2","article-title":"Spread of pathological tau proteins through communicating neurons in human Alzheimer\u2019s disease","volume":"11","author":"Vogel","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1177\/1533317508328602","article-title":"Reviews: Current Concepts in Alzheimer\u2019s Disease: A Multidisciplinary Review","volume":"24","author":"Minati","year":"2009","journal-title":"Am. J. Alzheimer\u2019s Dis. Other Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"559168","DOI":"10.3389\/fnsys.2020.559186","article-title":"Episodic Memories: How do the Hippocampus and the Entorhinal Ring Attractors Cooperate to Create Them?","volume":"14","year":"2020","journal-title":"Front. Syst. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/jnp.12219","article-title":"Temporal contiguity and ageing: The role of memory organization in cognitive decline","volume":"15","author":"Talamonti","year":"2021","journal-title":"J. Neuropsychol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3389\/fnsys.2017.00046","article-title":"Architecture of the Entorhinal Cortex A Review of Entorhinal Anatomy in Rodents with Some Comparative Notes","volume":"11","author":"Witter","year":"2017","journal-title":"Front. Syst. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1111\/j.1460-9568.2005.04567.x","article-title":"Extracellular matrix molecules and synaptic plasticity: Immunomapping of intracellular and secreted Reelin in the adult rat brain","volume":"23","author":"Galazo","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4407","DOI":"10.1073\/pnas.0914483107","article-title":"Lower number of cerebellar Purkinje neurons in psychosis is associated with reduced reelin expression","volume":"107","author":"Maloku","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.arr.2013.01.005","article-title":"Reelin signaling in development, maintenance, and plasticity of neural networks","volume":"12","author":"Stranahan","year":"2013","journal-title":"Ageing Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4636","DOI":"10.1523\/JNEUROSCI.5284-09.2010","article-title":"Reelin Regulates Postnatal Neurogenesis and Enhances Spine Hypertrophy and Long-Term Potentiation","volume":"30","author":"Pujadas","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.nlm.2011.03.009","article-title":"Interference with reelin signaling in the lateral entorhinal cortex impairs spatial memory","volume":"96","author":"Stranahan","year":"2011","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"804","DOI":"10.3389\/fnins.2020.00804","article-title":"Entorhinal and Transentorhinal Atrophy in Preclinical Alzheimer\u2019s Disease","volume":"14","author":"Kulason","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1523\/JNEUROSCI.16-14-04491.1996","article-title":"Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer\u2019s Disease","volume":"16","author":"Price","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.nbd.2016.05.012","article-title":"Reelin-immunoreactive neurons in entorhinal cortex layer II selectively express intracellular amyloid in early Alzheimer\u2019s disease","volume":"93","author":"Nagelhus","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/jnen\/nlz123","article-title":"From the Entorhinal Region via the Prosubiculum to the Dentate Fascia: Alzheimer Disease-Related Neurofibrillary Changes in the Temporal Allocortex","volume":"79","author":"Braak","year":"2020","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1093\/brain\/awaa068","article-title":"Medial temporal lobe connectivity and its associations with cognition in early Alzheimer\u2019s disease","volume":"143","author":"Berron","year":"2020","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/jnr.10554","article-title":"Altered levels of cerebrospinal fluid reelin in frontotemporal dementia and Alzheimer\u2019s disease","volume":"72","author":"Costell","year":"2003","journal-title":"J. Neurosci. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5573","DOI":"10.1073\/pnas.0601279103","article-title":"Reelin expression and glycosylation patterns are altered in Alzheimer\u2019s disease","volume":"103","author":"Burgaya","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1523\/JNEUROSCI.3758-06.2007","article-title":"Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer\u2019s Disease","volume":"27","author":"Chin","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.nbd.2009.12.006","article-title":"\u03b2-amyloid controls altered Reelin expression and processing in Alzheimer\u2019s disease","volume":"37","author":"Cotrufo","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"963","DOI":"10.3233\/JAD-2012-112069","article-title":"Reelin Depletion is an Early Phenomenon of Alzheimer\u2019s Pathology","volume":"30","author":"Herring","year":"2012","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"31646","DOI":"10.1038\/srep31646","article-title":"The \u03b2-amyloid peptide compromises Reelin signaling in Alzheimer\u2019s disease","volume":"6","author":"Balmaceda","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lid\u00f3n, L., Urrea, L., Llorens, F., Gil, V., Alvarez, I., Diez-Fairen, M., Aguilar, M., Pastor, P., Zerr, I., and Alcolea, D. (2020). Disease-Specific Changes in Reelin Protein and mRNA in Neurodegenerative Diseases. Cells, 9.","DOI":"10.3390\/cells9051252"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1016\/S0197-4580(98)00035-9","article-title":"Genetic Risk Factors in Japanese Alzheimer\u2019s Disease Patients: \u03b11-ACT, VLDLR, and ApoE","volume":"19","author":"Yamanaka","year":"1998","journal-title":"Neurobiol. Aging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3233\/JAD-2008-14308","article-title":"The RELN Locus in Alzheimer\u2019s Disease","volume":"14","author":"Seripa","year":"2008","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.bbrc.2015.05.044","article-title":"Functional enrichment analysis of three Alzheimer\u2019s disease genome-wide association studies identities DAB1 as a novel candidate liability\/protective gene","volume":"463","author":"Gao","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"328","DOI":"10.15252\/emmm.201505846","article-title":"Therapeutic correction of ApoER2 splicing in Alzheimer\u2019s disease mice using antisense oligonucleotides","volume":"8","author":"Hinrich","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3443","DOI":"10.1038\/ncomms4443","article-title":"Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer\u2019s disease","volume":"5","author":"Pujadas","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101743","DOI":"10.1016\/j.pneurobio.2019.101743","article-title":"Reelin reverts biochemical, physiological and cognitive alterations in mouse models of Tauopathy","volume":"186","author":"Rossi","year":"2020","journal-title":"Prog. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0896-6273(03)00819-5","article-title":"Reelin Promotes Hippocampal Dendrite Development through the VLDLR\/ApoER2-Dab1 Pathway","volume":"41","author":"Niu","year":"2004","journal-title":"Neuron"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10339","DOI":"10.1523\/JNEUROSCI.1917-08.2008","article-title":"The Reelin Signaling Pathway Promotes Dendritic Spine Development in Hippocampal Neurons","volume":"28","author":"Niu","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12051","DOI":"10.1523\/JNEUROSCI.1857-12.2012","article-title":"Cell-Autonomous Inactivation of the Reelin Pathway Impairs Adult Neurogenesis in the Hippocampus","volume":"32","author":"Teixeira","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4282","DOI":"10.1093\/cercor\/bhw216","article-title":"Reelin Regulates the Maturation of Dendritic Spines, Synaptogenesis and Glial Ensheathment of Newborn Granule Cells","volume":"26","author":"Bosch","year":"2016","journal-title":"Cereb. Cortex"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101307","DOI":"10.1016\/j.arr.2021.101307","article-title":"Re-emphasizing early Alzheimer\u2019s disease pathology starting in select entorhinal neurons, with a special focus on mitophagy","volume":"67","author":"Aman","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/S0896-6273(00)80861-2","article-title":"Direct Binding of Reelin to VLDL Receptor and ApoE Receptor 2 Induces Tyrosine Phosphorylation of Disabled-1 and Modulates Tau Phosphorylation","volume":"24","author":"Hiesberger","year":"1999","journal-title":"Neuron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1096\/fj.02-0434fje","article-title":"Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an Apolipoprotein E receptor\/disabled-1\/glycogen synthase kinase-3\u03b2 cascade","volume":"17","author":"Ohkubo","year":"2002","journal-title":"FASEB J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"40048","DOI":"10.7554\/eLife.40048","article-title":"Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer\u2019s disease","volume":"7","author":"Xian","year":"2018","journal-title":"eLife"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.cub.2019.11.027","article-title":"Fan Cells in Layer 2 of the Lateral Entorhinal Cortex Are Critical for Episodic-like Memory","volume":"30","author":"Vandrey","year":"2020","journal-title":"Curr. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1097\/00019052-200008000-00001","article-title":"Prodromal Alzheimer\u2019s disease\u2019: A more useful concept than mild cognitive impairment?","volume":"13","author":"Dubois","year":"2000","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s41583-019-0260-z","article-title":"Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories","volume":"21","author":"Hainmueller","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/nn.2185","article-title":"Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain","volume":"11","author":"Imayoshi","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6854","DOI":"10.1523\/JNEUROSCI.2976-17.2018","article-title":"Adult Neurogenesis Conserves Hippocampal Memory Capacity","volume":"38","author":"Alam","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/s41591-019-0375-9","article-title":"Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer\u2019s disease","volume":"25","author":"Cafini","year":"2019","journal-title":"Nat. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/nn1008-1124","article-title":"Regenerating your senses: Multiple roles for neurogenesis in the adult brain","volume":"11","author":"Frankland","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Sibbe, M., Kuner, E., Althof, D., and Frotscher, M. (2015). Stem- and Progenitor Cell Proliferation in the Dentate Gyrus of the Reeler Mouse. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119643"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1523\/JNEUROSCI.0988-17.2017","article-title":"Trajectory Analysis Unveils Reelin\u2019s Role in the Directed Migration of Granule Cells in the Dentate Gyrus","volume":"38","author":"Wang","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.cell.2013.05.002","article-title":"Dynamics of Hippocampal Neurogenesis in Adult Humans","volume":"153","author":"Spalding","year":"2013","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/ncomms2101","article-title":"Monosynaptic inputs to new neurons in the dentate gyrus","volume":"3","author":"Vivar","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"a018903","DOI":"10.1101\/cshperspect.a018903","article-title":"Maturation and Functional Integration of New Granule Cells into the Adult Hippocampus","volume":"8","author":"Toni","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.neuroimage.2009.05.037","article-title":"Neural correlates of Alzheimer\u2019s disease and mild cognitive impairment: A systematic and quantitative meta-analysis involving 1351 patients","volume":"47","author":"Schroeter","year":"2009","journal-title":"NeuroImage"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.neurobiolaging.2008.03.013","article-title":"White matter pathology isolates the hippocampal formation in Alzheimer\u2019s disease","volume":"31","author":"Salat","year":"2010","journal-title":"Neurobiol. Aging"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.stem.2018.11.006","article-title":"Does Adult Neurogenesis Persist in the Human Hippocampus?","volume":"23","author":"Paredes","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nature25975","article-title":"Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults","volume":"555","author":"Sorrells","year":"2018","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1523\/JNEUROSCI.0675-20.2020","article-title":"Evidences for Adult Hippocampal Neurogenesis in Humans","volume":"41","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1126\/science.1147851","article-title":"Magnetic Resonance Spectroscopy Identifies Neural Progenitor Cells in the Live Human Brain","volume":"318","author":"Manganas","year":"2007","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1000102","DOI":"10.4172\/2329-8847.1000102","article-title":"A New Scale for the Evaluation of Proactive and Retroactive Interference in Mild Cognitive Impairment and Early Alzheimer\u2019s Disease","volume":"1","author":"Curiel","year":"2013","journal-title":"J. Aging Sci."},{"key":"ref_57","first-page":"e12192","article-title":"The relationship of semantic intrusions to different etiological subtypes of MCI and cognitively healthy older adults","volume":"13","author":"Kitaigorodsky","year":"2021","journal-title":"Alzheimer\u2019s Dement. Diagn. Assess. Dis. Monit."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/nn.4056","article-title":"The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity","volume":"18","author":"Schlesiger","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/hipo.450030307","article-title":"Phase relationship between hippocampal place units and the EEG theta rhythm","volume":"3","author":"Recce","year":"1993","journal-title":"Hippocampus"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/s41593-018-0303-1","article-title":"Precise temporal memories are supported by the lateral entorhinal cortex in humans","volume":"22","author":"Montchal","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1017\/S1041610218000467","article-title":"The recency ratio as predictor of early MCI","volume":"30","author":"Bruno","year":"2018","journal-title":"Int. Psychogeriatr."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.actpsy.2013.03.001","article-title":"Impaired retention is responsible for temporal order memory deficits in mild cognitive impairment","volume":"143","author":"Gillis","year":"2013","journal-title":"Acta Psychol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/462\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:57:00Z","timestamp":1760169420000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,31]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23010462"],"URL":"https:\/\/doi.org\/10.3390\/ijms23010462","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,12,31]]}}}