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2000
Volume 21, Issue 5
  • ISSN: 1567-2050
  • E-ISSN: 1875-5828

Abstract

Alzheimer’s disease (AD) is a devastating neurological disorder that affects synaptic transmission between neurons. Several theories and concepts have been postulated to explain its etiology and pathogenesis. The disease has no cure, and the drugs available to manage AD symptoms provide only modest benefits. It originates in the brain’s entorhinal cortex (EC), with tau pathology that poses overt symptoms for decades and then spreads to other connected areas and networks to cause severe cognitive decline. Despite decades of research, the reason why the EC is the first region to be affected during AD pathophysiology remains unknown. The EC is well connected with surrounding areas to support the brain’s structural and functional integrity, participate in navigation, working memory, memory consolidation, olfaction, and olfactory-auditory coordination. These actions require massive energy expenditure, thus, the EC is extremely vulnerable to severe hypometabolism and an energy crisis. The crucial events/factors that make the EC vulnerable to pathological sequelae more than other brain regions have not been thoroughly explored. An in-depth analysis of available research on the role of the EC in AD could provide meaningful insights into the susceptibility of this region and its role in propagating AD. In this review article, we highlight how the functional complexities of the EC account for its vulnerability to AD.

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2025-07-24

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References

  1. NicholsE. SteinmetzJ.D. VollsetS.E. FukutakiK. ChalekJ. Abd-AllahF. AbdoliA. AbualhasanA. Abu-GharbiehE. AkramT.T. Al HamadH. AlahdabF. AlaneziF.M. AlipourV. AlmustanyirS. AmuH. AnsariI. ArablooJ. AshrafT. Astell-BurtT. AyanoG. Ayuso-MateosJ.L. BaigA.A. BarnettA. BarrowA. BauneB.T. BéjotY. BezabheW.M.M. BezabihY.M. BhagavathulaA.S. BhaskarS. BhattacharyyaK. BijaniA. BiswasA. BollaS.R. BoloorA. BrayneC. BrennerH. BurkartK. BurnsR.A. CámeraL.A. CaoC. CarvalhoF. Castro-de-AraujoL.F.S. Catalá-LópezF. CerinE. ChavanP.P. CherbuinN. ChuD-T. CostaV.M. CoutoR.A.S. DadrasO. DaiX. DandonaL. DandonaR. De la Cruz-GóngoraV. DhamnetiyaD. Dias da SilvaD. DiazD. DouiriA. EdvardssonD. EkholuenetaleM. El SayedI. El-JaafaryS.I. EskandariK. EskandariehS. EsmaeilnejadS. FaresJ. FaroA. FarooqueU. FeiginV.L. FengX. FereshtehnejadS-M. FernandesE. FerraraP. FilipI. FillitH. FischerF. GaidhaneS. GalluzzoL. GhashghaeeA. GhithN. GialluisiA. GilaniS.A. GlavanI-R. GnedovskayaE.V. GolechhaM. GuptaR. GuptaV.B. GuptaV.K. HaiderM.R. HallB.J. HamidiS. HanifA. HankeyG.J. HaqueS. HartonoR.K. HasaballahA.I. HasanM.T. HassanA. HayS.I. HayatK. HegazyM.I. HeidariG. Heidari-SoureshjaniR. HerteliuC. HousehM. HussainR. HwangB-F. IacovielloL. IavicoliI. IlesanmiO.S. IlicI.M. IlicM.D. IrvaniS.S.N. IsoH. IwagamiM. JabbarinejadR. JacobL. JainV. JayapalS.K. JayawardenaR. JhaR.P. JonasJ.B. JosephN. KalaniR. KandelA. KandelH. KarchA. KasaA.S. KassieG.M. KeshavarzP. KhanM.A.B. KhatibM.N. KhojaT.A.M. KhubchandaniJ. KimM.S. KimY.J. KisaA. KisaS. KivimäkiM. KoroshetzW.J. KoyanagiA. KumarG.A. KumarM. LakH.M. LeonardiM. LiB. LimS.S. LiuX. LiuY. LogroscinoG. LorkowskiS. LucchettiG. Lutzky SauteR. MagnaniF.G. MalikA.A. MassanoJ. MehndirattaM.M. MenezesR.G. MeretojaA. MohajerB. Mohamed IbrahimN. MohammadY. MohammedA. MokdadA.H. MondelloS. MoniM.A.A. MoniruzzamanM. MossieT.B. NagelG. NaveedM. NayakV.C. Neupane KandelS. NguyenT.H. OanceaB. OtstavnovN. OtstavnovS.S. OwolabiM.O. Panda-JonasS. Pashazadeh KanF. PasovicM. PatelU.K. PathakM. PeresM.F.P. PerianayagamA. PetersonC.B. PhillipsM.R. PinheiroM. PiradovM.A. PondC.D. PotashmanM.H. PottooF.H. PradaS.I. RadfarA. RaggiA. RahimF. RahmanM. RamP. RanasingheP. RawafD.L. RawafS. RezaeiN. RezapourA. RobinsonS.R. RomoliM. RoshandelG. SahathevanR. SahebkarA. SahraianM.A. SathianB. SattinD. SawhneyM. SaylanM. SchiavolinS. SeylaniA. ShaF. ShaikhM.A. ShajiK.S. ShannawazM. ShettyJ.K. ShigematsuM. ShinJ.I. ShiriR. SilvaD.A.S. SilvaJ.P. SilvaR. SinghJ.A. SkryabinV.Y. SkryabinaA.A. SmithA.E. SoshnikovS. SpurlockE.E. SteinD.J. SunJ. Tabarés-SeisdedosR. ThakurB. TimalsinaB. Tovani-PaloneM.R. TranB.X. TsegayeG.W. Valadan TahbazS. ValdezP.R. VenketasubramanianN. VlassovV. VuG.T. VuL.G. WangY-P. WimoA. WinklerA.S. YadavL. Yahyazadeh JabbariS.H. YamagishiK. YangL. YanoY. YonemotoN. YuC. YunusaI. ZadeyS. ZastrozhinM.S. ZastrozhinaA. ZhangZ-J. MurrayC.J.L. VosT. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019.Lancet Public Health202272e105e12510.1016/S2468‑2667(21)00249‑834998485
     [Google Scholar]
  2. GauthierS. Rosa-NetoP. MoraisJ.A. WebsterC. World Alzheimer Report 2021.2021Available from: https://www.alzint.org/u/World-Alzheimer-Report-2021.pdf
  3. KnopmanD.S. AmievaH. PetersenR.C. ChételatG. HoltzmanD.M. HymanB.T. NixonR.A. JonesD.T. Alzheimer disease.Nat. Rev. Dis. Primers2021713310.1038/s41572‑021‑00269‑y33986301
     [Google Scholar]
  4. LanoiseléeH.M. NicolasG. WallonD. Rovelet-LecruxA. LacourM. RousseauS. RichardA.C. PasquierF. Rollin-SillaireA. MartinaudO. Quillard-MuraineM. de la SayetteV. Boutoleau-BretonniereC. Etcharry-BouyxF. ChauviréV. SarazinM. le BerI. EpelbaumS. JonveauxT. RouaudO. CeccaldiM. FélicianO. GodefroyO. FormaglioM. CroisileB. AuriacombeS. ChamardL. VincentJ.L. SauvéeM. Marelli-TosiC. GabelleA. OzsancakC. ParienteJ. PaquetC. HannequinD. CampionD. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.PLoS Med.2017143e100227010.1371/journal.pmed.100227028350801
     [Google Scholar]
  5. CampionD. DumanchinC. HannequinD. DuboisB. BelliardS. PuelM. Thomas-AnterionC. MichonA. MartinC. CharbonnierF. RauxG. CamuzatA. PenetC. MesnageV. MartinezM. Clerget-DarpouxF. BriceA. FrebourgT. Early-onset autosomal dominant Alzheimer disease: Prevalence, genetic heterogeneity, and mutation spectrum.Am. J. Hum. Genet.199965366467010.1086/30255310441572
     [Google Scholar]
  6. 2021 Alzheimer's disease facts and figures.Alzheimers Dement.202117332740610.1002/alz.1232833756057
     [Google Scholar]
  7. TarczylukM.A. NagelD.A. ParriH.R. TseE.H.Y. BrownJ.E. ColemanM.D. HillE.J. Amyloid β 1-42 induces hypometabolism in human stem cell-derived neuron and astrocyte networks.J. Cereb. Blood Flow Metab.20153581348135710.1038/jcbfm.2015.5825853906
     [Google Scholar]
  8. SivanesanS. TanA. RajadasJ. Pathogenesis of Abeta oligomers in synaptic failure.Curr. Alzheimer Res.201310331632310.2174/156720501131003001123036017
     [Google Scholar]
  9. MorrisG.P. ClarkI.A. VisselB. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease.Acta Neuropathol. Commun.20142113510.1186/s40478‑014‑0135‑525231068
     [Google Scholar]
  10. KametaniF. HasegawaM. Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer’s Disease.Front. Neurosci.2018122510.3389/fnins.2018.0002529440986
     [Google Scholar]
  11. StrubleR.G. AlaT. PatryloP.R. BrewerG.J. YanX.X. Is brain amyloid production a cause or a result of dementia of the Alzheimer’s type?J. Alzheimers Dis.201022239339910.3233/JAD‑2010‑10084620847431
     [Google Scholar]
  12. CorreiaS.C. SantosR.X. PerryG. ZhuX. MoreiraP.I. SmithM.A. Insulin-resistant brain state: The culprit in sporadic Alzheimer’s disease?Ageing Res. Rev.201110226427310.1016/j.arr.2011.01.00121262392
     [Google Scholar]
  13. CostantiniL.C. BarrL.J. VogelJ.L. HendersonS.T. Hypometabolism as a therapeutic target in Alzheimer’s disease.BMC Neurosci.20089S2S1610.1186/1471‑2202‑9‑S2‑S1619090989
     [Google Scholar]
  14. CastellaniR.J. ZhuX. LeeH. MoreiraP.I. PerryG. SmithM.A. Neuropathology and treatment of Alzheimer disease: did we lose the forest for the trees?Expert Rev. Neurother.20077547348510.1586/14737175.7.5.47317492899
     [Google Scholar]
  15. Mondragón-RodríguezS. Basurto-IslasG. LeeH. PerryG. ZhuX. CastellaniR.J. SmithM.A. Causes versus effects: The increasing complexities of Alzheimer’s disease pathogenesis.Expert Rev. Neurother.201010568369110.1586/ern.10.2720420489
     [Google Scholar]
  16. PulidoC. RyanT.A. Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals.Sci. Adv.2021749eabi902710.1126/sciadv.abi902734860552
     [Google Scholar]
  17. OlajideO.J. SuvantoM.E. ChapmanC.A. Molecular mechanisms of neurodegeneration in the entorhinal cortex that underlie its selective vulnerability during the pathogenesis of Alzheimer’s disease.Biol. Open2021101bio05679610.1242/bio.05679633495355
     [Google Scholar]
  18. StranahanA.M. MattsonM.P. Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer’s disease.Neural Plast.201020101810.1155/2010/10819021331296
     [Google Scholar]
  19. Gómez-IslaT. PriceJ.L. McKeelD.W.Jr MorrisJ.C. GrowdonJ.H. HymanB.T. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease.J. Neurosci.199616144491450010.1523/JNEUROSCI.16‑14‑04491.19968699259
     [Google Scholar]
  20. SenutM.C. RoudierM. DavousP. Fallet-BiancoC. LamourY. Senile dementia of the Alzheimer type: Is there a correlation between entorhinal cortex and dentate gyrus lesions?Acta Neuropathol.199182430631510.1007/BF003088171759562
     [Google Scholar]
  21. MatsudaH. Cerebral blood flow and metabolic abnormalities in Alzheimer’s disease.Ann. Nucl. Med.2001152859210.1007/BF0298859611448080
     [Google Scholar]
  22. deToledo-MorrellL. StoubT.R. BulgakovaM. WilsonR.S. BennettD.A. LeurgansS. WuuJ. TurnerD.A. MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD.Neurobiol. Aging20042591197120310.1016/j.neurobiolaging.2003.12.00715312965
     [Google Scholar]
  23. IgarashiK.M. Entorhinal cortex dysfunction in Alzheimer’s disease.Trends Neurosci.202346212413610.1016/j.tins.2022.11.00636513524
     [Google Scholar]
  24. KentS.A. Spires-JonesT.L. DurrantC.S. The physiological roles of tau and Aβ: Implications for Alzheimer’s disease pathology and therapeutics.Acta Neuropathol.2020140441744710.1007/s00401‑020‑02196‑w32728795
     [Google Scholar]
  25. SiahaanV. KrattenmacherJ. HymanA.A. DiezS. Hernández-VegaA. LanskyZ. BraunM. Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes.Nat. Cell Biol.20192191086109210.1038/s41556‑019‑0374‑631481789
     [Google Scholar]
  26. HongS. Beja-GlasserV.F. NfonoyimB.M. FrouinA. LiS. RamakrishnanS. MerryK.M. ShiQ. RosenthalA. BarresB.A. LemereC.A. SelkoeD.J. StevensB. Complement and microglia mediate early synapse loss in Alzheimer mouse models.Science2016352628671271610.1126/science.aad837327033548
     [Google Scholar]
  27. WalshD.M. KlyubinI. FadeevaJ.V. CullenW.K. AnwylR. WolfeM.S. RowanM.J. SelkoeD.J. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo .Nature2002416688053553910.1038/416535a11932745
     [Google Scholar]
  28. LeeJ.S. ParkY.H. ParkS. YoonU. ChoeY. CheonB.K. HahnA. ChoS.H. KimS.J. KimJ.P. JungY.H. ParkK.C. KimH.J. JangH. NaD.L. SeoS.W. Distinct brain regions in physiological and pathological brain aging.Front. Aging Neurosci.20191114710.3389/fnagi.2019.0014731275140
     [Google Scholar]
  29. FrisoniG.B. PievaniM. TestaC. SabattoliF. BrescianiL. BonettiM. BeltramelloA. HayashiK.M. TogaA.W. ThompsonP.M. The topography of grey matter involvement in early and late onset Alzheimer’s disease.Brain2007130372073010.1093/brain/awl37717293358
     [Google Scholar]
  30. OssenkoppeleR. Cohn-SheehyB.I. La JoieR. VogelJ.W. MöllerC. LehmannM. van BerckelB.N.M. SeeleyW.W. PijnenburgY.A. Gorno-TempiniM.L. KramerJ.H. BarkhofF. RosenH.J. van der FlierW.M. JagustW.J. MillerB.L. ScheltensP. RabinoviciG.D. Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer's disease.Hum. Brain Mapp.201536114421443710.1002/hbm.2292726260856
     [Google Scholar]
  31. FjellA.M. McEvoyL. HollandD. DaleA.M. WalhovdK.B. What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus.Prog. Neurobiol.2014117204010.1016/j.pneurobio.2014.02.00424548606
     [Google Scholar]
  32. NelsonP.T. SmithC.D. AbnerE.L. WilfredB.J. WangW.X. NeltnerJ.H. BakerM. FardoD.W. KryscioR.J. ScheffS.W. JichaG.A. JellingerK.A. Van EldikL.J. SchmittF.A. Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease.Acta Neuropathol.2013126216117710.1007/s00401‑013‑1154‑123864344
     [Google Scholar]
  33. AttwellD. LaughlinS.B. An energy budget for signaling in the grey matter of the brain.J. Cereb. Blood Flow Metab.200121101133114510.1097/00004647‑200110000‑0000111598490
     [Google Scholar]
  34. RangarajuV. LauterbachM. SchumanE.M. Spatially stable mitochondrial compartments fuel local translation during plasticity.Cell20191761-27384.e1510.1016/j.cell.2018.12.01330612742
     [Google Scholar]
  35. LaughlinS.B. de Ruyter van SteveninckR.R. AndersonJ.C. The metabolic cost of neural information.Nat. Neurosci.199811364110.1038/23610195106
     [Google Scholar]
  36. LaurinD. VerreaultR. LindsayJ. MacPhersonK. RockwoodK. Physical activity and risk of cognitive impairment and dementia in elderly persons.Arch. Neurol.200158349850410.1001/archneur.58.3.49811255456
     [Google Scholar]
  37. LegdeurN. HeymansM.W. ComijsH.C. HuismanM. MaierA.B. VisserP.J. Age dependency of risk factors for cognitive decline.BMC Geriatr.201818118710.1186/s12877‑018‑0876‑230126373
     [Google Scholar]
  38. Ammassari-TeuleM. Early-occurring dendritic spines alterations in mouse models of Alzheimer’s disease inform on primary causes of neurodegeneration.Front. Synaptic Neurosci.20201256661510.3389/fnsyn.2020.56661533013348
     [Google Scholar]
  39. DorostkarM.M. ZouC. Blazquez-LlorcaL. HermsJ. Analyzing dendritic spine pathology in Alzheimer’s disease: Problems and opportunities.Acta Neuropathol.2015130111910.1007/s00401‑015‑1449‑526063233
     [Google Scholar]
  40. MijalkovM. VolpeG. Fernaud-EspinosaI. DeFelipeJ. PereiraJ.B. Merino-SerraisP. Dendritic spines are lost in clusters in Alzheimer’s disease.Sci. Rep.20211111235010.1038/s41598‑021‑91726‑x34117272
     [Google Scholar]
  41. Reza-ZaldivarE.E. Hernández-SápiensM.A. MinjarezB. Gómez-PinedoU. Sánchez-GonzálezV.J. Márquez-AguirreA.L. Canales-AguirreA.A. Dendritic spine and synaptic plasticity in Alzheimer’s disease: A focus on MicroRNA.Front. Cell Dev. Biol.2020825510.3389/fcell.2020.0025532432108
     [Google Scholar]
  42. RungeK. CardosoC. de ChevignyA. Dendritic spine plasticity: Function and mechanisms.Front. Synaptic Neurosci.2020123610.3389/fnsyn.2020.0003632982715
     [Google Scholar]
  43. YuW. LuB. Synapses and dendritic spines as pathogenic targets in Alzheimer’s disease.Neural Plast.201220121810.1155/2012/24715022474602
     [Google Scholar]
  44. WalkerC.K. HerskowitzJ.H. Dendritic spines: Mediators of cognitive resilience in aging and Alzheimer’s disease.Neuroscientist202127548750510.1177/107385842094596432812494
     [Google Scholar]
  45. BorosB.D. GreathouseK.M. GentryE.G. CurtisK.A. BirchallE.L. GearingM. HerskowitzJ.H. Dendritic spines provide cognitive resilience against Alzheimer's disease.Ann. Neurol.201782460261410.1002/ana.2504928921611
     [Google Scholar]
  46. MeldolesiJ. Post-synapses in the brain: Role of dendritic and spine structures.Biomedicines2022108185910.3390/biomedicines1008185936009405
     [Google Scholar]
  47. MuddapuV.R. DharshiniS.A.P. ChakravarthyV.S. GromihaM.M. Neurodegenerative diseases – Is metabolic deficiency the root cause?Front. Neurosci.20201421310.3389/fnins.2020.0021332296300
     [Google Scholar]
  48. BaikS.H. KangS. LeeW. ChoiH. ChungS. KimJ.I. Mook-JungI. A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease.Cell Metab.2019303493507.e610.1016/j.cmet.2019.06.00531257151
     [Google Scholar]
  49. SivanesanS. ChangE. HowellM.D. RajadasJ. Amyloid protein aggregates: New clients for mitochondrial energy production in the brain?FEBS J.2020287163386339510.1111/febs.1522531981301
     [Google Scholar]
  50. SivanesanS. MundugaruR. RajadasJ. Possible clues for brain energy translation via endolysosomal trafficking of APP-CTFs in Alzheimer’s disease.Oxid. Med. Cell. Longev.201820181276483110.1155/2018/276483130420907
     [Google Scholar]
  51. JohnsonE.C.B. DammerE.B. DuongD.M. PingL. ZhouM. YinL. HigginbothamL.A. GuajardoA. WhiteB. TroncosoJ.C. ThambisettyM. MontineT.J. LeeE.B. TrojanowskiJ.Q. BeachT.G. ReimanE.M. HaroutunianV. WangM. SchadtE. ZhangB. DicksonD.W. Ertekin-TanerN. GoldeT.E. PetyukV.A. De JagerP.L. BennettD.A. WingoT.S. RangarajuS. HajjarI. ShulmanJ.M. LahJ.J. LeveyA.I. SeyfriedN.T. Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation.Nat. Med.202026576978010.1038/s41591‑020‑0815‑632284590
     [Google Scholar]
  52. MuddapuV.R. ChakravarthyV.S. Influence of energy deficiency on the subcellular processes of Substantia Nigra Pars Compacta cell for understanding Parkinsonian neurodegeneration.Sci. Rep.2021111175410.1038/s41598‑021‑81185‑933462293
     [Google Scholar]
  53. HoltD.J. ÖngürD. WrightC.I. DickersonB.C. RauchS.L. Neuroanatomical systems relevant to neuropsychiatric disorders.2008975995
     [Google Scholar]
  54. EichenbaumH. On the integration of space, time, and memory.Neuron20179551007101810.1016/j.neuron.2017.06.03628858612
     [Google Scholar]
  55. SchultzH. SommerT. PetersJ. The role of the human entorhinal cortex in a representational account of memory.Front. Hum. Neurosci.2015962810.3389/fnhum.2015.0062826635581
     [Google Scholar]
  56. GerevichZ. KovácsR. LiottaA. Hasam-HendersonL.A. WehL. WallachI. BerndtN. Metabolic implications of axonal demyelination and its consequences for synchronized network activity: An in silico and in vitro study.J. Cereb. Blood Flow Metab.20234391571158710.1177/0271678X23117074637125487
     [Google Scholar]
  57. MohandasE. RajmohanV. RaghunathB. Neurobiology of Alzheimer′s disease.Indian J. Psychiatry2009511556110.4103/0019‑5545.4490819742193
     [Google Scholar]
  58. PetracheA.L. RajulawallaA. ShiA. WetzelA. SaitoT. SaidoT.C. HarveyK. AliA.B. Aberrant excitatory–inhibitory synaptic mechanisms in entorhinal cortex microcircuits during the pathogenesis of Alzheimer’s disease.Cereb. Cortex20192941834185010.1093/cercor/bhz01630766992
     [Google Scholar]
  59. AchardS. BullmoreE. Efficiency and cost of economical brain functional networks.PLOS Comput. Biol.200732e1710.1371/journal.pcbi.003001717274684
     [Google Scholar]
  60. TerniB. BoadaJ. Portero-OtinM. PamplonaR. FerrerI. Mitochondrial ATP-synthase in the entorhinal cortex is a target of oxidative stress at stages I/II of Alzheimer’s disease pathology.Brain Pathol.201020122223310.1111/j.1750‑3639.2009.00266.x19298596
     [Google Scholar]
  61. Domínguez-ÁlvaroM. Montero-CrespoM. Blazquez-LlorcaL. Plaza-AlonsoS. Cano-AstorgaN. DeFelipeJ. Alonso-NanclaresL. 3D Analysis of the Synaptic Organization in the Entorhinal Cortex in Alzheimer’s Disease.eNeuro202183ENEURO.0504-20.202110.1523/ENEURO.0504‑20.202134039651
     [Google Scholar]
  62. GrubmanA. ChewG. OuyangJ.F. SunG. ChooX.Y. McLeanC. SimmonsR.K. BuckberryS. Vargas-LandinD.B. PoppeD. PfluegerJ. ListerR. RackhamO.J.L. PetrettoE. PoloJ.M. A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation.Nat. Neurosci.201922122087209710.1038/s41593‑019‑0539‑431768052
     [Google Scholar]
  63. LengK. LiE. EserR. PiergiesA. SitR. TanM. NeffN. LiS.H. RodriguezR.D. SuemotoC.K. LeiteR.E.P. EhrenbergA.J. PasqualucciC.A. SeeleyW.W. SpinaS. HeinsenH. GrinbergL.T. KampmannM. Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease.Nat. Neurosci.202124227628710.1038/s41593‑020‑00764‑733432193
     [Google Scholar]
  64. JabaudonD. ShniderS.J. TischfieldD.J. GalazoM.J. MacklisJ.D. RORβ induces barrel-like neuronal clusters in the developing neocortex.Cereb. Cortex2012225996100610.1093/cercor/bhr18221799210
     [Google Scholar]
  65. OishiK. AramakiM. NakajimaK. Mutually repressive interaction between Brn1/2 and Rorb contributes to the establishment of neocortical layer 2/3 and layer 4.Proc. Natl. Acad. Sci. USA2016113123371337610.1073/pnas.151594911326951672
     [Google Scholar]
  66. AxmacherN. HenselerM.M. JensenO. WeinreichI. ElgerC.E. FellJ. Cross-frequency coupling supports multi-item working memory in the human hippocampus.Proc. Natl. Acad. Sci. USA201010773228323310.1073/pnas.091153110720133762
     [Google Scholar]
  67. TortA.B.L. KomorowskiR.W. MannsJ.R. KopellN.J. EichenbaumH. Theta–gamma coupling increases during the learning of item–context associations.Proc. Natl. Acad. Sci. USA200910649209422094710.1073/pnas.091133110619934062
     [Google Scholar]
  68. NakazonoT. JunH. Blurton-JonesM. GreenK.N. IgarashiK.M. Gamma oscillations in the entorhinal-hippocampal circuit underlying memory and dementia.Neurosci. Res.2018129404610.1016/j.neures.2018.02.00229438778
     [Google Scholar]
  69. DiehlG.W. HonO.J. LeutgebS. LeutgebJ.K. Grid and nongrid cells in medial entorhinal cortex represent spatial location and environmental features with complementary coding schemes.Neuron20179418392.e610.1016/j.neuron.2017.03.00428343867
     [Google Scholar]
  70. HaftingT. FyhnM. MoldenS. MoserM.B. MoserE.I. Microstructure of a spatial map in the entorhinal cortex.Nature2005436705280180610.1038/nature0372115965463
     [Google Scholar]
  71. SargoliniF. FyhnM. HaftingT. McNaughtonB.L. WitterM.P. MoserM.B. MoserE.I. Conjunctive representation of position, direction, and velocity in entorhinal cortex.Science2006312577475876210.1126/science.112557216675704
     [Google Scholar]
  72. DomnisoruC. KinkhabwalaA.A. TankD.W. Membrane potential dynamics of grid cells.Nature2013495744019920410.1038/nature1197323395984
     [Google Scholar]
  73. SunC. KitamuraT. YamamotoJ. MartinJ. PignatelliM. KitchL.J. SchnitzerM.J. TonegawaS. Distinct speed dependence of entorhinal island and ocean cells, including respective grid cells.Proc. Natl. Acad. Sci. USA2015112309466947110.1073/pnas.151166811226170279
     [Google Scholar]
  74. LiptonP.A. EichenbaumH. Complementary roles of hippocampus and medial entorhinal cortex in episodic memory.Neural Plast.200820081810.1155/2008/25846718615199
     [Google Scholar]
  75. SosaM. GiocomoL.M. Navigating for reward.Nat. Rev. Neurosci.202122847248710.1038/s41583‑021‑00479‑z34230644
     [Google Scholar]
  76. MoserE.I. MoserM.B. RoudiY. Network mechanisms of grid cells.Philos. Trans. R. Soc. Lond. B Biol. Sci.201436916352012051110.1098/rstb.2012.051124366126
     [Google Scholar]
  77. KropffE. CarmichaelJ.E. MoserM.B. MoserE.I. Speed cells in the medial entorhinal cortex.Nature2015523756141942410.1038/nature1462226176924
     [Google Scholar]
  78. HowardL.R. JavadiA.H. YuY. MillR.D. MorrisonL.C. KnightR. LoftusM.M. StaskuteL. SpiersH.J. The hippocampus and entorhinal cortex encode the path and Euclidean distances to goals during navigation.Curr. Biol.201424121331134010.1016/j.cub.2014.05.00124909328
     [Google Scholar]
  79. ErdemU.M. HasselmoM.E. A biologically inspired hierarchical goal directed navigation model.J. Physiol. Paris20141081283710.1016/j.jphysparis.2013.07.00223891644
     [Google Scholar]
  80. KrausB.J. RobinsonR.J.II WhiteJ.A. EichenbaumH. HasselmoM.E. Hippocampal “time cells”: Time versus path integration.Neuron20137861090110110.1016/j.neuron.2013.04.01523707613
     [Google Scholar]
  81. PastollH. RamsdenH.L. NolanM.F. Intrinsic electrophysiological properties of entorhinal cortex stellate cells and their contribution to grid cell firing fields.Front. Neural Circuits201261710.3389/fncir.2012.0001722536175
     [Google Scholar]
  82. UmbachG. KantakP. JacobsJ. KahanaM. PfeifferB.E. SperlingM. LegaB. Time cells in the human hippocampus and entorhinal cortex support episodic memory.Proc. Natl. Acad. Sci. USA202011745284632847410.1073/pnas.201325011733109718
     [Google Scholar]
  83. TsaoA. SugarJ. LuL. WangC. KnierimJ.J. MoserM.B. MoserE.I. Integrating time from experience in the lateral entorhinal cortex.Nature20185617721576210.1038/s41586‑018‑0459‑630158699
     [Google Scholar]
  84. GerleiK.Z. BrownC.M. SürmeliG. NolanM.F. Deep entorhinal cortex: From circuit organization to spatial cognition and memory.Trends Neurosci.2021441187688710.1016/j.tins.2021.08.00334593254
     [Google Scholar]
  85. BurakY. FieteI.R. Accurate path integration in continuous attractor network models of grid cells.PLOS Comput. Biol.200952e100029110.1371/journal.pcbi.100029119229307
     [Google Scholar]
  86. BushD. BarryC. MansonD. BurgessN. Using grid cells for navigation.Neuron201587350752010.1016/j.neuron.2015.07.00626247860
     [Google Scholar]
  87. StemmlerM. MathisA. HerzA.V.M. Connecting multiple spatial scales to decode the population activity of grid cells.Sci. Adv.2015111e150081610.1126/science.150081626824061
     [Google Scholar]
  88. FuchsE.C. NeitzA. PinnaR. MelzerS. CaputiA. MonyerH. Local and distant input controlling excitation in layer II of the medial entorhinal cortex.Neuron201689119420810.1016/j.neuron.2015.11.02926711115
     [Google Scholar]
  89. SürmeliG. MarcuD.C. McClureC. GardenD.L.F. PastollH. NolanM.F. Molecularly defined circuitry reveals input-output segregation in deep layers of the medial entorhinal cortex.Neuron20158851040105310.1016/j.neuron.2015.10.04126606996
     [Google Scholar]
  90. VargaC. LeeS.Y. SolteszI. Target-selective GABAergic control of entorhinal cortex output.Nat. Neurosci.201013782282410.1038/nn.257020512133
     [Google Scholar]
  91. KitamuraT. PignatelliM. SuhJ. KoharaK. YoshikiA. AbeK. TonegawaS. Island cells control temporal association memory.Science2014343617389690110.1126/science.124463424457215
     [Google Scholar]
  92. AlonsoA. García-AusttE. Neuronal sources of theta rhythm in the entorhinal cortex of the rat.Exp. Brain Res.198767350250910.1007/BF002472833653312
     [Google Scholar]
  93. AlonsoA. LlinásR.R. Subthreshold Na+-dependent theta-like rhythmicity in stellate cells of entorhinal cortex layer II.Nature1989342624617517710.1038/342175a02812013
     [Google Scholar]
  94. LlinásR.R. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function.Science198824248861654166410.1126/science.30594973059497
     [Google Scholar]
  95. TraubR.D. MilesR. WongR.K.S. Model of the origin of rhythmic population oscillations in the hippocampal slice.Science198924348961319132510.1126/science.26467152646715
     [Google Scholar]
  96. LaczóM. MartinkovicL. LerchO. WienerJ.M. KalinovaJ. MatuskovaV. NedelskaZ. VyhnalekM. HortJ. LaczóJ. Different profiles of spatial navigation deficits in Alzheimer’s disease biomarker-positive versus biomarker-negative older aAdults with amnestic mild cognitive impairment.Front. Aging Neurosci.20221488677810.3389/fnagi.2022.88677835721017
     [Google Scholar]
  97. GrienbergerC. MageeJ.C. Entorhinal cortex directs learning-related changes in CA1 representations.Nature2022611793655456210.1038/s41586‑022‑05378‑636323779
     [Google Scholar]
  98. WagnerI.C. GraichenL.P. TodorovaB. LüttigA. OmerD.B. StanglM. LammC. Entorhinal grid-like codes and time-locked network dynamics track others navigating through space.Nat. Commun.202314123110.1038/s41467‑023‑35819‑336720865
     [Google Scholar]
  99. BilashO.M. ChavlisS. JohnsonC.D. PoiraziP. BasuJ. Lateral entorhinal cortex inputs modulate hippocampal dendritic excitability by recruiting a local disinhibitory microcircuit.Cell Rep.202342111196210.1016/j.celrep.2022.11196236640337
     [Google Scholar]
  100. PriceJ.L. Olfactory higher centers anatomy.201010.1016/B978‑008045046‑9.01692‑2
     [Google Scholar]
  101. BiellaG. de CurtisM. Olfactory inputs activate the medial entorhinal cortex via the hippocampus.J. Neurophysiol.20008341924193110.1152/jn.2000.83.4.192410758103
     [Google Scholar]
  102. KerrK.M. AgsterK.L. FurtakS.C. BurwellR.D. Functional neuroanatomy of the parahippocampal region: The lateral and medial entorhinal areas.Hippocampus200717969770810.1002/hipo.2031517607757
     [Google Scholar]
  103. ShimshekD.R. BusT. KimJ. MihaljevicA. MackV. SeeburgP.H. SprengelR. SchaeferA.T. Enhanced odor discrimination and impaired olfactory memory by spatially controlled switch of AMPA receptors.PLoS Biol.2005311e35410.1371/journal.pbio.003035416216087
     [Google Scholar]
  104. EichenbaumH. SchoenbaumG. YoungB. BunseyM. Functional organization of the hippocampal memory system.Proc. Natl. Acad. Sci. USA19969324135001350710.1073/pnas.93.24.135008942963
     [Google Scholar]
  105. BitzenhoferS.H. WesteindeE.A. ZhangH.X.B. IsaacsonJ.S. Rapid odor processing by layer 2 subcircuits in lateral entorhinal cortex.eLife202211e7506510.7554/eLife.7506535129439
     [Google Scholar]
  106. KoselK.C. Van HoesenG.W. WestJ.R. Olfactory bulb projections to the parahippocampal area of the rat.J. Comp. Neurol.1981198346748210.1002/cne.9019803077240454
     [Google Scholar]
  107. DavisJ.L. EichenbaumH. Olfaction: A model system for computational neuroscienceMIT press1991
     [Google Scholar]
  108. WuT. LiS. DuD. LiR. LiuP. YinZ. ZhangH. QiaoY. LiA. Olfactory–auditory sensory integration in the lateral entorhinal cortex.Prog. Neurobiol.202322110239910.1016/j.pneurobio.2022.10239936581184
     [Google Scholar]
  109. DaulatzaiM.A. Olfactory dysfunction: its early temporal relationship and neural correlates in the pathogenesis of Alzheimer’s disease.J. Neural Transm. (Vienna)2015122101475149710.1007/s00702‑015‑1404‑625944089
     [Google Scholar]
  110. WitterM.P. DoanT.P. JacobsenB. NilssenE.S. OharaS. Architecture of the entorhinal cortex A review of entorhinal anatomy in rodents with some comparative notes.Front. Syst. Neurosci.2017114610.3389/fnsys.2017.0004628701931
     [Google Scholar]
  111. JovéM. Mota-MartorellN. TorresP. AyalaV. Portero-OtinM. FerrerI. PamplonaR. The Causal role of lipoxidative damage in mitochondrial bioenergetic dysfunction linked to alzheimer’s disease pathology.Life (Basel)202111538810.3390/life1105038833923074
     [Google Scholar]
  112. HymanB.T. Van HoesenG.W. DamasioA.R. BarnesC.L. Alzheimer’s disease: Cell-specific pathology isolates the hippocampal formation.Science198422546671168117010.1126/science.64741726474172
     [Google Scholar]
  113. BraakH. BraakE. Neuropathological stageing of Alzheimer-related changes.Acta Neuropathol.199182423925910.1007/BF003088091759558
     [Google Scholar]
  114. OlsenR.K. YeungL.K. Noly-GandonA. D’AngeloM.C. KacolljaA. SmithV.M. RyanJ.D. BarenseM.D. Human anterolateral entorhinal cortex volumes are associated with cognitive decline in aging prior to clinical diagnosis.Neurobiol. Aging20175719520510.1016/j.neurobiolaging.2017.04.02528578804
     [Google Scholar]
  115. KordowerJ.H. ChuY. StebbinsG.T. DeKoskyS.T. CochranE.J. BennettD. MufsonE.J. Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment.Ann. Neurol.200149220221310.1002/1531‑8249(20010201)49:2<202::AID‑ANA40>3.0.CO;2‑311220740
     [Google Scholar]
  116. Kobro-FlatmoenA. Lagartos-DonateM.J. AmanY. EdisonP. WitterM.P. FangE.F. Re-emphasizing early Alzheimer’s disease pathology starting in select entorhinal neurons, with a special focus on mitophagy.Ageing Res. Rev.20216710130710.1016/j.arr.2021.10130733621703
     [Google Scholar]
  117. XuY. JackC.R.Jr O’BrienP.C. KokmenE. SmithG.E. IvnikR.J. BoeveB.F. TangalosR.G. PetersenR.C. Usefulness of MRI measures of entorhinal cortex versus hippocampus in AD.Neurology20005491760176710.1212/WNL.54.9.176010802781
     [Google Scholar]
  118. DuA.T. SchuffN. KramerJ.H. GanzerS. ZhuX.P. JagustW.J. MillerB.L. ReedB.R. MungasD. YaffeK. ChuiH.C. WeinerM.W. Higher atrophy rate of entorhinal cortex than hippocampus in AD.Neurology200462342242710.1212/01.WNL.0000106462.72282.9014872024
     [Google Scholar]
  119. DuA.T. SchuffN. ZhuX.P. JagustW.J. MillerB.L. ReedB.R. KramerJ.H. MungasD. YaffeK. ChuiH.C. WeinerM.W. Atrophy rates of entorhinal cortex in AD and normal aging.Neurology200360348148610.1212/01.WNL.0000044400.11317.EC12578931
     [Google Scholar]
  120. BerggaardN. WitterM.P. van der WantJ.J.L. GABAA receptor subunit α3 in network dynamics in the medial entorhinal cortex.Front. Syst. Neurosci.2019131010.3389/fnsys.2019.0001030930755
     [Google Scholar]
  121. HarrisS.S. WolfF. De StrooperB. BuscheM.A. Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease.Neuron2020107341743510.1016/j.neuron.2020.06.00532579881
     [Google Scholar]
  122. FuH. RodriguezG.A. HermanM. EmraniS. NahmaniE. BarrettG. FigueroaH.Y. GoldbergE. HussainiS.A. DuffK.E. Tau pathology induces excitatory neuron loss, grid cell dysfunction, and spatial memory deficits reminiscent of early Alzheimer’s disease.Neuron2017933533541.e510.1016/j.neuron.2016.12.02328111080
     [Google Scholar]
  123. Llamas-RodríguezJ. OltmerJ. GreveD.N. WilliamsE. SlepnevaN. WangR. ChampionS. Lang-OrsiniM. FischlB. FroschM.P. van der KouweA.J.W. AugustinackJ.C. Entorhinal subfield vulnerability to neurofibrillary tangles in aging and the preclinical stage of Alzheimer’s disease.J. Alzheimers Dis.20228731379139910.3233/JAD‑21556735491780
     [Google Scholar]
  124. PesoldC. ImpagnatielloF. PisuM.G. UzunovD.P. CostaE. GuidottiA. CarunchoH.J. Reelin is preferentially expressed in neurons synthesizing γ-aminobutyric acid in cortex and hippocampus of adult rats.Proc. Natl. Acad. Sci. USA19989563221322610.1073/pnas.95.6.32219501244
     [Google Scholar]
  125. Kobro-FlatmoenA. WitterM.P. Neuronal chemo-architecture of the entorhinal cortex: A comparative review.Eur. J. Neurosci.201950103627366210.1111/ejn.1451131293027
     [Google Scholar]
  126. BeffertU. WeeberE.J. DurudasA. QiuS. MasiulisI. SweattJ.D. LiW.P. AdelmannG. FrotscherM. HammerR.E. HerzJ. Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2.Neuron200547456757910.1016/j.neuron.2005.07.00716102539
     [Google Scholar]
  127. Kobro-FlatmoenA. NagelhusA. WitterM.P. Reelin-immunoreactive neurons in entorhinal cortex layer II selectively express intracellular amyloid in early Alzheimer’s disease.Neurobiol. Dis.20169317218310.1016/j.nbd.2016.05.01227195475
     [Google Scholar]
  128. BeffertU. MorfiniG. BockH.H. ReynaH. BradyS.T. HerzJ. Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3β.J. Biol. Chem.200227751499584996410.1074/jbc.M20920520012376533
     [Google Scholar]
  129. ZhaoR. GrunkeS.D. WoodC.A. PerezG.A. ComstockM. LiM.H. SinghA.K. ParkK.W. JankowskyJ.L. Activity disruption causes degeneration of entorhinal neurons in a mouse model of Alzheimer’s circuit dysfunction.eLife202211e8381310.7554/eLife.8381336468693
     [Google Scholar]
  130. LiuC.C. KanekiyoT. XuH. BuG. BuG. Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy.Nat. Rev. Neurol.20139210611810.1038/nrneurol.2012.26323296339
     [Google Scholar]
  131. SalamiA. AdolfssonR. AnderssonM. BlennowK. LundquistA. AdolfssonA.N. SchöllM. ZetterbergH. NybergL. Association of APOE ɛ4 and plasma p-tau181 with preclinical Alzheimer’s disease and longitudinal change in hippocampus function.J. Alzheimers Dis.20228531309132010.3233/JAD‑21067334924376
     [Google Scholar]
  132. ShiY. YamadaK. LiddelowS.A. SmithS.T. ZhaoL. LuoW. TsaiR.M. SpinaS. GrinbergL.T. RojasJ.C. GallardoG. WangK. RohJ. RobinsonG. FinnM.B. JiangH. SullivanP.M. BaufeldC. WoodM.W. SutphenC. McCueL. XiongC. Del-AguilaJ.L. MorrisJ.C. CruchagaC. FaganA.M. MillerB.L. BoxerA.L. SeeleyW.W. ButovskyO. BarresB.A. PaulS.M. HoltzmanD.M. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.Nature2017549767352352710.1038/nature2401628959956
     [Google Scholar]
  133. XianX. PohlkampT. DurakoglugilM.S. WongC.H. BeckJ.K. Lane-DonovanC. PlattnerF. HerzJ. Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease.eLife20187e4004810.7554/eLife.4004830375977
     [Google Scholar]
  134. ThornsV. LicastroF. MasliahE. Locally reduced levels of acidic FGF lead to decreased expression of 28-kDa calbindin and contribute to the selective vulnerability of the neurons in the entorhinal cortex in Alzheimer’s disease.Neuropathology200121320321110.1046/j.1440‑1789.2001.00399.x11666017
     [Google Scholar]
  135. ChinJ. MassaroC.M. PalopJ.J. ThwinM.T. YuG.Q. Bien-LyN. BenderA. MuckeL. Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer’s disease.J. Neurosci.200727112727273310.1523/JNEUROSCI.3758‑06.200717360894
     [Google Scholar]
  136. ShuS. ZhuH. TangN. ChenW. LiX. LiH. PeiL. LiuD. MuY. TianQ. ZhuL.Q. LuY. Selective degeneration of entorhinal-CA1 synapses in Alzheimer’s disease via activation of DAPK1.J. Neurosci.20163642108431085210.1523/JNEUROSCI.2258‑16.201627798139
     [Google Scholar]
  137. BraakH. ThalD.R. GhebremedhinE. Del TrediciK. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years.J. Neuropathol. Exp. Neurol.2011701196096910.1097/NEN.0b013e318232a37922002422
     [Google Scholar]
  138. KaufmanS.K. Del TrediciK. ThomasT.L. BraakH. DiamondM.I. Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART.Acta Neuropathol.20181361576710.1007/s00401‑018‑1855‑629752551
     [Google Scholar]
  139. BerchtoldN.C. SabbaghM.N. BeachT.G. KimR.C. CribbsD.H. CotmanC.W. Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer’s disease.Neurobiol. Aging20143591961197210.1016/j.neurobiolaging.2014.03.03124786631
     [Google Scholar]
  140. CabréR. JovéM. NaudíA. AyalaV. Piñol-RipollG. Gil-VillarM.P. Dominguez-GonzalezM. ObisÈ. BerdunR. Mota-MartorellN. Portero-OtínM. FerrerI. PamplonaR. Specific metabolomics adaptations define a differential regional vulnerability in the adult human cerebral cortex.Front. Mol. Neurosci.2016913810.3389/fnmol.2016.0013828008307
     [Google Scholar]
  141. KapogiannisD. AvgerinosK.I. Brain glucose and ketone utilization in brain aging and neurodegenerative diseases.Int Rev Neurobiol20201547911010.1016/bs.irn.2020.03.015.
     [Google Scholar]
  142. YinF. SanchetiH. PatilI. CadenasE. Energy metabolism and inflammation in brain aging and Alzheimer’s disease.Free Radic. Biol. Med.201610010812210.1016/j.freeradbiomed.2016.04.20027154981
     [Google Scholar]
  143. KhanU.A. LiuL. ProvenzanoF.A. BermanD.E. ProfaciC.P. SloanR. MayeuxR. DuffK.E. SmallS.A. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease.Nat. Neurosci.201417230431110.1038/nn.360624362760
     [Google Scholar]
  144. PickettE.K. HenstridgeC.M. AllisonE. PitstickR. PoolerA. WegmannS. CarlsonG. HymanB.T. Spires-JonesT.L. Spread of tau down neural circuits precedes synapse and neuronal loss in the rTgTauEC mouse model of early Alzheimer's disease.Synapse2017716e2196510.1002/syn.2196528196395
     [Google Scholar]
  145. WegmannS. BennettR.E. DelormeL. RobbinsA.B. HuM. MacKenzieD. KirkM.J. SchiantarelliJ. TunioN. AmaralA.C. FanZ. NichollsS. HudryE. HymanB.T. Experimental evidence for the age dependence of tau protein spread in the brain.Sci. Adv.201956eaaw640410.1126/sciadv.aaw640431249873
     [Google Scholar]
  146. SettiS.E. ReedM.N. Network activity changes in the pathophysiology of Alzheimer’s disease: The role of aging and early entorhinal cortex dysfunction.Metab. Brain Dis.202237228929810.1007/s11011‑021‑00848‑834591222
     [Google Scholar]
  147. MaassA. LockhartS.N. HarrisonT.M. BellR.K. MellingerT. SwinnertonK. BakerS.L. RabinoviciG.D. JagustW.J. Entorhinal tau pathology, episodic memory decline, and neurodegeneration in aging.J. Neurosci.201838353054310.1523/JNEUROSCI.2028‑17.201729192126
     [Google Scholar]
  148. StromA. IaccarinoL. EdwardsL. Lesman-SegevO.H. Soleimani-MeigooniD.N. PhamJ. BakerS.L. LandauS.M. JagustW.J. MillerB.L. RosenH.J. Gorno-TempiniM.L. RabinoviciG.D. La JoieR. Cortical hypometabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease.Brain2022145271372810.1093/brain/awab29434373896
     [Google Scholar]
  149. LaurettiE. LiJ-G. Di MecoA. PraticòD. Glucose deficit triggers tau pathology and synaptic dysfunction in a tauopathy mouse model.Transl. Psychiatry201771e1020e102010.1038/tp.2016.29628140402
     [Google Scholar]
  150. SnyderB. ShellB. CunninghamJ.T. CunninghamR.L. Chronic intermittent hypoxia induces oxidative stress and inflammation in brain regions associated with early-stage neurodegeneration.Physiol. Rep.201759e1325810.14814/phy2.1325828473320
     [Google Scholar]
  151. OrigliaN. CriscuoloC. ArancioO. YanS.S. DomeniciL. RAGE inhibition in microglia prevents ischemia-dependent synaptic dysfunction in an amyloid-enriched environment.J. Neurosci.201434268749876010.1523/JNEUROSCI.0141‑14.201424966375
     [Google Scholar]
  152. JanelsinsM.C. MastrangeloM.A. OddoS. LaFerlaF.M. FederoffH.J. BowersW.J. Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer’s disease mice.J. Neuroinflammation2005212310.1186/1742‑2094‑2‑2316232318
     [Google Scholar]
  153. LiuW. ChenS. RaoX. YangY. ChenX. YuL. The inflammatory gene PYCARD of the entorhinal cortex as an early diagnostic target for Alzheimer’s disease.Biomedicines202311119410.3390/biomedicines1101019436672701
     [Google Scholar]
  154. Astillero-LopezV. Gonzalez-RodriguezM. Villar-CondeS. Flores-CuadradoA. Martinez-MarcosA. Ubeda-BanonI. Saiz-SanchezD. Neurodegeneration and astrogliosis in the entorhinal cortex in Alzheimer’s disease: Stereological layer-specific assessment and proteomic analysis.Alzheimers Dement.202218122468248010.1002/alz.1258035142030
     [Google Scholar]
  155. FerrerI. Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer’s disease and Creutzfeldt–Jakob’s disease.Neuropathol. Appl. Neurobiol.200228644145110.1046/j.1365‑2990.2002.t01‑1‑00410.x12445160
     [Google Scholar]
  156. Armand-UgonM. AnsoleagaB. BerjaouiS. FerrerI. Reduced mitochondrial activity is early and steady in the entorhinal cortex but it is mainly unmodified in the frontal cortex in Alzheimer’s disease.Curr. Alzheimer Res.201714121327133428474567
     [Google Scholar]
  157. RuanL. ZhouC. JinE. KucharavyA. ZhangY. WenZ. FlorensL. LiR. Cytosolic proteostasis through importing of misfolded proteins into mitochondria.Nature2017543764544344610.1038/nature2169528241148
     [Google Scholar]
  158. GriffinJ.W.D. BradshawP.C. Amino acid catabolism in Alzheimer’s disease brain: Friend or Foe?Oxid. Med. Cell. Longev.201720171547279210.1155/2017/547279228261376
     [Google Scholar]
  159. BlázquezE. Hurtado-CarneiroV. LeBaut-AyusoY. VelázquezE. García-GarcíaL. Gómez-OliverF. Ruiz-AlbusacJ.M. ÁvilaJ. PozoM.Á. Significance of brain glucose hypometabolism, altered insulin signal transduction, and insulin resistance in several neurological diseases.Front. Endocrinol. (Lausanne)20221387330110.3389/fendo.2022.87330135615716
     [Google Scholar]
  160. ChenZ. ZhongC. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies.Prog. Neurobiol.2013108214310.1016/j.pneurobio.2013.06.00423850509
     [Google Scholar]
  161. GibsonG.E. HirschJ.A. CirioR.T. JordanB.D. FonzettiP. ElderJ. Abnormal thiamine-dependent processes in Alzheimer’s Disease. Lessons from diabetes.Mol. Cell. Neurosci.201355172510.1016/j.mcn.2012.09.00122982063
     [Google Scholar]
  162. KapogiannisD. MattsonM.P. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease.Lancet Neurol.201110218719810.1016/S1474‑4422(10)70277‑521147038
     [Google Scholar]
  163. CunnaneS.C. TrushinaE. MorlandC. PrigioneA. CasadesusG. AndrewsZ.B. BealM.F. BergersenL.H. BrintonR.D. de la MonteS. EckertA. HarveyJ. JeggoR. JhamandasJ.H. KannO. la CourC.M. MartinW.F. MithieuxG. MoreiraP.I. MurphyM.P. NaveK.A. NurielT. OlietS.H.R. SaudouF. MattsonM.P. SwerdlowR.H. MillanM.J. Brain energy rescue: An emerging therapeutic concept for neurodegenerative disorders of ageing.Nat. Rev. Drug Discov.202019960963310.1038/s41573‑020‑0072‑x32709961
     [Google Scholar]
  164. LiM. LarsenP.A. Single-cell sequencing of entorhinal cortex reveals widespread disruption of neuropeptide networks in Alzheimer’s disease.Alzheimers Dement.20231983575359210.1002/alz.1297936825405
     [Google Scholar]
  165. Area-GomezE. LarreaD. PeraM. AgrawalR.R. GuilfoyleD.N. PirhajiL. ShannonK. ArainH.A. AshokA. ChenQ. DillmanA.A. FigueroaH.Y. CooksonM.R. GrossS.S. FraenkelE. DuffK.E. NurielT. APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice.Sci. Rep.2020101427710.1038/s41598‑020‑61142‑832152337
     [Google Scholar]
  166. YuH. LinX. WangD. ZhangZ. GuoY. RenX. XuB. YuanJ. LiuJ. SpencerP.S. WangJ.Z. YangX. Mitochondrial molecular abnormalities revealed by proteomic analysis of hippocampal organelles of mice triple transgenic for Alzheimer disease.Front. Mol. Neurosci.2018117410.3389/fnmol.2018.0007429593495
     [Google Scholar]
  167. SchöllM. LockhartS.N. SchonhautD.R. O’NeilJ.P. JanabiM. OssenkoppeleR. BakerS.L. VogelJ.W. FariaJ. SchwimmerH.D. RabinoviciG.D. JagustW.J. PET imaging of tau deposition in the aging human brain.Neuron201689597198210.1016/j.neuron.2016.01.02826938442
     [Google Scholar]
  168. MurphyC. Olfactory and other sensory impairments in Alzheimer disease.Nat. Rev. Neurol.2019151112410.1038/s41582‑018‑0097‑530532084
     [Google Scholar]
/content/journals/car/10.2174/0115672050324909240823104209
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Multifunctional Tasks and an Energy Crisis are Crucial Players in Determining the Vulnerability of the Entorhinal Cortex to Early Damage in Alzheimer’s Disease
Curr Alzheimer Res 21, 295 (2024); https://doi.org/10.2174/0115672050324909240823104209
/content/journals/car/10.2174/0115672050324909240823104209
/content/journals/car/10.2174/0115672050324909240823104209
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  • Article Type:     Review Article
Keyword(s): Alzheimer’s disease; amyloid beta; entorhinal cortex; lateral entorhinal cortex; medial entorhinal cortex; neuritic plaques; neurofibrillary tangles; tau

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