{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:11:22Z","timestamp":1785323482466,"version":"3.55.0"},"reference-count":102,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T00:00:00Z","timestamp":1641859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"MIUR","doi-asserted-by":"publisher","award":["PRIN-20175C22WM"],"award-info":[{"award-number":["PRIN-20175C22WM"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CARIPARO","award":["Excellence project 2017 (2018\/113)"],"award-info":[{"award-number":["Excellence project 2017 (2018\/113)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>For Alzheimer\u2019s disease (AD), aging is the main risk factor, but whether cognitive impairments due to aging resemble early AD deficits is not yet defined. When working with mouse models of AD, the situation is just as complicated, because only a few studies track the progression of the disease at different ages, and most ignore how the aging process affects control mice. In this work, we addressed this problem by comparing the aging process of PS2APP (AD) and wild-type (WT) mice at the level of spontaneous brain electrical activity under anesthesia. Using local field potential recordings, obtained with a linear probe that traverses the posterior parietal cortex and the entire hippocampus, we analyzed how multiple electrical parameters are modified by aging in AD and WT mice. With this approach, we highlighted AD specific features that appear in young AD mice prior to plaque deposition or that are delayed at 12 and 16 months of age. Furthermore, we identified aging characteristics present in WT mice but also occurring prematurely in young AD mice. In short, we found that reduction in the relative power of slow oscillations (SO) and Low\/High power imbalance are linked to an AD phenotype at its onset. The loss of SO connectivity and cortico-hippocampal coupling between SO and higher frequencies as well as the increase in UP-state and burst durations are found in young AD and old WT mice. We show evidence that the aging process is accelerated by the mutant PS2 itself and discuss such changes in relation to amyloidosis and gliosis.<\/jats:p>","DOI":"10.3390\/cells11020238","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T14:05:07Z","timestamp":1641909907000},"page":"238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Accelerated Aging Characterizes the Early Stage of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9110-1055","authenticated-orcid":false,"given":"Alessandro","family":"Leparulo","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Padua, Via U. Bassi 58\/B, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Bisio","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padua, Via U. Bassi 58\/B, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Redolfi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padua, Via U. Bassi 58\/B, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tullio","family":"Pozzan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padua, Via U. Bassi 58\/B, 35131 Padua, Italy"},{"name":"Neuroscience Institute-Italian National Research Council (CNR), Via U. Bassi 58\/B, 35131 Padua, Italy"},{"name":"Venetian Institute of Molecular Medicine (VIMM), Via G. Orus 2B, 35129 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0389-8023","authenticated-orcid":false,"given":"Stefano","family":"Vassanelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padua, Via U. Bassi 58\/B, 35131 Padua, Italy"},{"name":"Padua Neuroscience Center (PNC), University of Padua, Via G. Orus 2B, 35129 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9816-7751","authenticated-orcid":false,"given":"Cristina","family":"Fasolato","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padua, Via U. Bassi 58\/B, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102386","DOI":"10.1016\/j.isci.2021.102386","article-title":"EEG alterations during wake and sleep in mild cognitive impairment and Alzheimer\u2019s disease","volume":"24","author":"Scarpelli","year":"2021","journal-title":"iScience"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S0197-4580(00)00153-6","article-title":"Quantitative electroencephalography in mild cognitive impairment: Longitudinal changes and possible prediction of Alzheimer\u2019s disease","volume":"21","author":"Jelic","year":"2000","journal-title":"Neurobiol. Aging"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"491","DOI":"10.3389\/fncel.2015.00491","article-title":"Precocious Alterations of Brain Oscillatory Activity in Alzheimer\u2019s Disease: A Window of Opportunity for Early Diagnosis and Treatment","volume":"9","author":"Hamm","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.neurobiolaging.2005.07.021","article-title":"Prediction of longitudinal cognitive decline in normal elderly with subjective complaints using electrophysiological imaging","volume":"27","author":"Prichep","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.neuron.2017.11.028","article-title":"Alzheimer\u2019s Disease: From Firing Instability to Homeostasis Network Collapse","volume":"97","author":"Frere","year":"2018","journal-title":"Neuron"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nrn.2016.141","article-title":"Network abnormalities and interneuron dysfunction in Alzheimer disease","volume":"17","author":"Palop","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.neuron.2014.10.024","article-title":"Dendritic Structural Degeneration Is Functionally Linked to Cellular Hyperexcitability in a Mouse Model of Alzheimer\u2019s Disease","volume":"84","author":"Justus","year":"2014","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41593-018-0080-x","article-title":"Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer\u2019s disease","volume":"21","author":"Styr","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1146\/annurev-neuro-080317-061725","article-title":"What Happens with the Circuit in Alzheimer\u2019s Disease in Mice and Humans?","volume":"41","author":"Zott","year":"2018","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e13189","DOI":"10.1111\/acel.13189","article-title":"Mechanisms by which autophagy regulates memory capacity in ageing","volume":"19","author":"Torromino","year":"2020","journal-title":"Aging Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.cub.2018.12.021","article-title":"Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline","volume":"29","author":"Glatigny","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"108985","DOI":"10.1016\/j.celrep.2021.108985","article-title":"Dietary spermidine improves cognitive function","volume":"35","author":"Schroeder","year":"2021","journal-title":"Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chiarini, A., Armato, U., Hu, P., and Dal Pr\u00e0, I. (2020). Danger-Sensing\/Patten Recognition Receptors and Neuroinflammation in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239036"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nn.4222","article-title":"Microglial brain region\u2212dependent diversity and selective regional sensitivities to aging","volume":"19","author":"Grabert","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/s41419-020-03137-x","article-title":"Age-related cerebral small vessel disease and inflammaging","volume":"11","author":"Li","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.bbr.2014.02.005","article-title":"mTOR and autophagy in normal brain aging and caloric restriction ameliorating age-related cognition deficits","volume":"264","author":"Yang","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.neuron.2020.06.005","article-title":"Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer\u2019s Disease","volume":"107","author":"Harris","year":"2020","journal-title":"Neuron"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.conb.2020.02.003","article-title":"Amyloid \u03b2-protein and beyond: The path forward in Alzheimer\u2019s disease","volume":"61","author":"Walsh","year":"2020","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101372","DOI":"10.1016\/j.arr.2021.101372","article-title":"Neuronal excitation\/inhibition imbalance: Core element of a translational perspective on Alzheimer pathophysiology","volume":"69","author":"Busche","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"136106","DOI":"10.1016\/j.neulet.2021.136106","article-title":"Brain network features based on theta-gamma cross-frequency coupling connections in EEG for emotion recognition","volume":"761","author":"Wang","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8740","DOI":"10.1073\/pnas.1206171109","article-title":"Critical role of soluble amyloid-\u03b2 for early hippocampal hyperactivity in a mouse model of Alzheimer\u2019s disease","volume":"109","author":"Busche","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.neurobiolaging.2016.10.027","article-title":"Early hippocampal hyperexcitability in PS2APP mice: Role of mutant PS2 and APP","volume":"50","author":"Fontana","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1111\/ejn.12233","article-title":"Alterations in hippocampal network oscillations and theta-gamma coupling arise before A\u03b2 overproduction in a mouse model of Alzheimer\u2019s disease","volume":"37","author":"Goutagny","year":"2013","journal-title":"Eur. J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bezzina, C., Verret, L., Juan, C., Remaud, J., Halley, H., Rampon, C., and Dahan, L. (2015). Early Onset of Hypersynchronous Network Activity and Expression of a Marker of Chronic Seizures in the Tg2576 Mouse Model of Alzheimer\u2019s Disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119910"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nm.4330","article-title":"Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer\u2019s disease","volume":"23","author":"Lam","year":"2017","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"E2895","DOI":"10.1073\/pnas.1121081109","article-title":"Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer\u2019s disease model","volume":"109","author":"Sanchez","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.cell.2012.02.046","article-title":"Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model","volume":"149","author":"Verret","year":"2012","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.neuron.2016.04.009","article-title":"Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples","volume":"90","author":"Gillespie","year":"2016","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/nature20587","article-title":"Gamma frequency entrainment attenuates amyloid load and modifies microglia","volume":"540","author":"Iaccarino","year":"2016","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.tins.2015.09.001","article-title":"Neural Cross-Frequency Coupling: Connecting Architectures, Mechanisms, and Functions","volume":"38","author":"Hyafil","year":"2015","journal-title":"Trends Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1002\/hipo.23309","article-title":"Cross-regional phase amplitude coupling supports the encoding of episodic memories","volume":"31","author":"Wang","year":"2021","journal-title":"Hippocampus"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"756661","DOI":"10.3389\/fpsyg.2021.756661","article-title":"Working Memory and Cross-Frequency Coupling of Neuronal Oscillations","volume":"12","author":"Abubaker","year":"2021","journal-title":"Front. Psychol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102033","DOI":"10.1016\/j.pneurobio.2021.102033","article-title":"Causal role of cross-frequency coupling in distinct components of cognitive control","volume":"202","author":"Riddle","year":"2021","journal-title":"Prog. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e05352","DOI":"10.7554\/eLife.05352","article-title":"Corticothalamic phase synchrony and cross-frequency coupling predict human memory formation","volume":"3","author":"Zaehle","year":"2014","journal-title":"eLife"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1093\/cercor\/bhu232","article-title":"Slow-Theta-to-Gamma Phase-Amplitude Coupling in Human Hippocampus Supports the Formation of New Episodic Memories","volume":"26","author":"Lega","year":"2016","journal-title":"Cereb. Cortex"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1159\/000513511","article-title":"Odour Retrieval Processing in Mice: Cholinergic Modulation of Oscillatory Coupling in Olfactory Bulb-Piriform Networks","volume":"80","author":"Ahnaou","year":"2021","journal-title":"Neuropsychobiology"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kastanenka, K.V., Hou, S.S., Shakerdge, N., Logan, R., Feng, D., Wegmann, S., Chopra, V., Hawkes, J.M., Chen, X., and Bacskai, B.J. (2017). Optogenetic Restoration of Disrupted Slow Oscillations Halts Amyloid Deposition and Restores Calcium Homeostasis in an Animal Model of Alzheimer\u2019s Disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170275"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.cell.2019.02.014","article-title":"Multi-sensory Gamma Stimulation Ameliorates Alzheimer\u2019s-Associated Pathology and Improves Cognition","volume":"177","author":"Martorell","year":"2019","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101878","DOI":"10.1016\/j.pneurobio.2020.101878","article-title":"Neural oscillations and brain stimulation in Alzheimer\u2019s disease","volume":"194","author":"Jafari","year":"2020","journal-title":"Prog. Neurobiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.neuron.2018.11.042","article-title":"The Hippocampus and Neocortical Inhibitory Engrams Protect against Memory Interference","volume":"101","author":"Koolschijn","year":"2019","journal-title":"Neuron"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Leparulo, A., Mahmud, M., Scremin, E., Pozzan, T., Vassanelli, S., and Fasolato, C. (2019). Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer\u2019s Disease. Cells, 9.","DOI":"10.3390\/cells9010054"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1038\/nn.4137","article-title":"Rescue of long-range circuit dysfunction in Alzheimer\u2019s disease models","volume":"18","author":"Busche","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7111","DOI":"10.1523\/JNEUROSCI.0260-17.2017","article-title":"Promoting Sleep Oscillations and Their Functional Coupling by Transcranial Stimulation Enhances Memory Consolidation in Mild Cognitive Impairment","volume":"37","author":"Ladenbauer","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"E6868","DOI":"10.1073\/pnas.1607289113","article-title":"Human cortical\u2013hippocampal dialogue in wake and slow-wave sleep","volume":"113","author":"Mitra","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1159\/000170884","article-title":"Expression of Transgenic APP mRNA Is the Key Determinant for Beta-Amyloid Deposition in PS2APP Transgenic Mice","volume":"6","author":"Ozmen","year":"2009","journal-title":"Neurodegener. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1093\/cercor\/bhs105","article-title":"Increased Cortical and Thalamic Excitability in Freely Moving APPswe\/PS1dE9 Mice Modeling Epileptic Activity Associated with Alzheimer\u2019s Disease","volume":"23","author":"Gurevicius","year":"2013","journal-title":"Cereb. Cortex"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8989","DOI":"10.1523\/JNEUROSCI.23-26-08989.2003","article-title":"PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation","volume":"23","author":"Richards","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"E6972","DOI":"10.1073\/pnas.1703309114","article-title":"Low-frequency hippocampal\u2013cortical activity drives brain-wide resting-state functional MRI connectivity","volume":"114","author":"Chan","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.1523\/JNEUROSCI.3648-15.2016","article-title":"Synaptic Mechanisms of Memory Consolidation during Sleep Slow Oscillations","volume":"36","author":"Wei","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3109\/15622971003637637","article-title":"Slow-wave sleep and the consolidation of long-term memory","volume":"11","author":"Born","year":"2010","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.neuron.2017.11.020","article-title":"Old Brains Come Uncoupled in Sleep: Slow Wave-Spindle Synchrony, Brain Atrophy, and Forgetting","volume":"97","author":"Helfrich","year":"2018","journal-title":"Neuron"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3389\/fnbeh.2015.00103","article-title":"Acute intracerebral treatment with amyloid-beta (1-42) alters the profile of neuronal oscillations that accompany LTP induction and results in impaired LTP in freely behaving rats","volume":"9","author":"Kalweit","year":"2015","journal-title":"Front. Behav. Neurosci."},{"key":"ref_54","first-page":"8869526","article-title":"Acute Effects of Two Different Species of Amyloid-\u03b2 on Oscillatory Activity and Synaptic Plasticity in the Commissural CA3-CA1 Circuit of the Hippocampus","volume":"2020","author":"Valderrama","year":"2020","journal-title":"Neural Plast."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.cell.2019.08.040","article-title":"Competing Roles of Slow Oscillations and Delta Waves in Memory Consolidation versus Forgetting","volume":"179","author":"Kim","year":"2019","journal-title":"Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.jneumeth.2010.06.019","article-title":"Cross-correlation of instantaneous amplitudes of field potential oscillations: A straightforward method to estimate the directionality and lag between brain areas","volume":"191","author":"Adhikari","year":"2010","journal-title":"J. Neurosci. Methods"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.neuron.2013.01.031","article-title":"Making Waves: Initiation and Propagation of Corticothalamic Ca2+ Waves In Vivo","volume":"77","author":"Stroh","year":"2013","journal-title":"Neuron"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3252","DOI":"10.1523\/JNEUROSCI.13-08-03252.1993","article-title":"A novel slow (<1 Hz) oscillation of neocortical neurons in vivo: Depolarizing and hyperpolarizing components","volume":"13","author":"Steriade","year":"1993","journal-title":"J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1152\/jn.1997.77.4.1697","article-title":"Spontaneous Subthreshold Membrane Potential Fluctuations and Action Potential Variability of Rat Corticostriatal and Striatal Neurons In Vivo","volume":"77","author":"Stern","year":"1997","journal-title":"J. Neurophysiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nature01614","article-title":"Attractor dynamics of network UP states in the neocortex","volume":"423","author":"Cossart","year":"2003","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nature22324","article-title":"Maintenance of persistent activity in a frontal thalamocortical loop","volume":"545","author":"Guo","year":"2017","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5169","DOI":"10.1073\/pnas.0700222104","article-title":"Differential responses of hippocampal subfields to cortical up\u2013down states","volume":"104","author":"Hahn","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1111\/j.1460-9568.2007.05885.x","article-title":"Slow oscillation of membrane currents mediated by glutamatergic inputs of rat somatosensory cortical neurons: In vivo patch-clamp analysis","volume":"26","author":"Doi","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5915","DOI":"10.1523\/JNEUROSCI.0447-07.2007","article-title":"V Development and Plasticity of Spontaneous Activity and Up States in Cortical Organotypic Slices","volume":"27","author":"Johnson","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/79848","article-title":"Cellular and network mechanisms of rhythmic recurrent activity in neocortex","volume":"3","author":"McCormick","year":"2000","journal-title":"Nat. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"10388","DOI":"10.1523\/JNEUROSCI.23-32-10388.2003","article-title":"Barrages of Synaptic Activity Control the Gain and Sensitivity of Cortical Neurons","volume":"23","author":"Shu","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S0166-2236(96)10070-9","article-title":"Bursts as a unit of neural information: Making unreliable synapses reliable","volume":"20","author":"Lisman","year":"1997","journal-title":"Trends Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nn.3376","article-title":"Spike bursts increase amyloid-\u03b2 40\/42 ratio by inducing a presenilin-1 conformational change","volume":"16","author":"Dolev","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1111\/j.1474-9726.2012.00858.x","article-title":"Ca 2+ dysregulation in neurons from transgenic mice expressing mutant presenilin 2","volume":"11","author":"Kipanyula","year":"2012","journal-title":"Aging Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1080\/15548627.2019.1596489","article-title":"PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca2+ homeostasis","volume":"15","author":"Fedeli","year":"2019","journal-title":"Autophagy"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1093\/brain\/awq033","article-title":"Alzheimer\u2019s disease phenotypes and genotypes associated with mutations in presenilin 2","volume":"133","author":"Jayadev","year":"2010","journal-title":"Brain"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/2051-5960-2-61","article-title":"Intracellular A\u03b2 pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: A multidimensional study","volume":"2","author":"Iulita","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00401-018-1922-z","article-title":"Evidence of intraneuronal A\u03b2 accumulation preceding tau pathology in the entorhinal cortex","volume":"136","author":"Welikovitch","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"548","DOI":"10.2967\/jnumed.118.217703","article-title":"Early and Longitudinal Microglial Activation but Not Amyloid Accumulation Predicts Cognitive Outcome in PS2APP Mice","volume":"60","author":"Focke","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1523\/JNEUROSCI.1871-19.2019","article-title":"Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the A\u03b242:A\u03b240 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer\u2019s Mouse Model","volume":"40","author":"Meilandt","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3389\/fnagi.2017.00008","article-title":"Increase of TREM2 during Aging of an Alzheimer\u2019s Disease Mouse Model Is Paralleled by Microglial Activation and Amyloidosis","volume":"9","author":"Brendel","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fgene.2017.00191","article-title":"Perspective: Is Random Monoallelic Expression a Contributor to Phenotypic Variability of Autosomal Dominant Disorders?","volume":"8","author":"Gui","year":"2017","journal-title":"Front. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5346","DOI":"10.1038\/s41467-021-25492-9","article-title":"Accelerated functional brain aging in pre-clinical familial Alzheimer\u2019s disease","volume":"12","author":"Gonneaud","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2859","DOI":"10.1084\/jem.20171320","article-title":"Gpr158 mediates osteocalcin\u2019s regulation of cognition","volume":"214","author":"Khrimian","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/nature13163","article-title":"REST and stress resistance in ageing and Alzheimer\u2019s disease","volume":"507","author":"Lu","year":"2014","journal-title":"Nature"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s12035-014-8877-4","article-title":"Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels","volume":"52","author":"Kaja","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Pizzo, P., Basso, E., Filadi, R., Greotti, E., Leparulo, A., Pendin, D., Redolfi, N., Rossini, M., Vajente, N., and Pozzan, T. (2020). Presenilin-2 and Calcium Handling: Molecules, Organelles, Cells and Brain Networks. Cells, 9.","DOI":"10.3390\/cells9102166"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.bbrc.2016.08.088","article-title":"Astroglial calcium signalling in Alzheimer\u2019s disease","volume":"483","author":"Verkhratsky","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"E2675","DOI":"10.1073\/pnas.1520759113","article-title":"Astrocytes regulate cortical state switching in vivo","volume":"113","author":"Poskanzer","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"18453","DOI":"10.1073\/pnas.1112378108","article-title":"Astrocytic regulation of cortical UP states","volume":"108","author":"Poskanzer","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ceca.2019.02.005","article-title":"Familial Alzheimer\u2019s disease-linked presenilin mutants and intracellular Ca2+ handling: A single-organelle, FRET-based analysis","volume":"79","author":"Greotti","year":"2019","journal-title":"Cell Calcium"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1073\/pnas.1100735108","article-title":"Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk","volume":"108","author":"Zampese","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1152\/jn.00915.2004","article-title":"Modeling Sleep and Wakefulness in the Thalamocortical System","volume":"93","author":"Hill","year":"2005","journal-title":"J. Neurophysiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3389\/fncir.2015.00088","article-title":"The Slow Oscillation in Cortical and Thalamic Networks: Mechanisms and Functions","volume":"9","author":"Neske","year":"2016","journal-title":"Front. Neural Circuits"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Rigotto, G., Zentilin, L., Pozzan, T., and Basso, E. (2021). Effects of Mild Excitotoxic Stimulus on Mitochondria Ca2+ Handling in Hippocampal Cultures of a Mouse Model of Alzheimer\u2019s Disease. Cells, 10.","DOI":"10.3390\/cells10082046"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1016\/j.celrep.2020.01.060","article-title":"Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer\u2019s Disease-Related Models","volume":"30","author":"Rossi","year":"2020","journal-title":"Cell Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.ceca.2016.06.008","article-title":"When, where and how? Focus on neuronal calcium dysfunctions in Alzheimer\u2019s Disease","volume":"60","author":"Agostini","year":"2016","journal-title":"Cell Calcium"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/j.bbamcr.2018.07.018","article-title":"Calcium signaling in Alzheimer\u2019s disease & therapies","volume":"1865","author":"Tong","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1016\/j.neuron.2021.06.030","article-title":"Thalamus mediates neocortical Down state transition via GABAB-receptor-targeting interneurons","volume":"109","author":"Hay","year":"2021","journal-title":"Neuron"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.neurobiolaging.2016.04.016","article-title":"Corticothalamic network dysfunction and behavioral deficits in a mouse model of Alzheimer\u2019s disease","volume":"44","author":"Hazra","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.brainres.2017.09.014","article-title":"Corticothalamic network dysfunction and Alzheimer\u2019s disease","volume":"1702","author":"Jagirdar","year":"2019","journal-title":"Brain Res."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Mart\u00edn-Belmonte, A., Aguado, C., Alfaro-Ru\u00edz, R., Moreno-Mart\u00ednez, A.E., de la Ossa, L., Mart\u00ednez-Hern\u00e1ndez, J., Buisson, A., Shigemoto, R., Fukazawa, Y., and Luj\u00e1n, R. (2020). Density of GABAB Receptors Is Reduced in Granule Cells of the Hippocampus in a Mouse Model of Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072459"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41593-020-0624-8","article-title":"Disease-associated astrocytes in Alzheimer\u2019s disease and aging","volume":"23","author":"Habib","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/s41593-020-00783-4","article-title":"Reactive astrocyte nomenclature, definitions, and future directions","volume":"24","author":"Escartin","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.bbr.2005.02.007","article-title":"Age-related impairments in operant DMTP performance in the PS2APP mouse, a transgenic mouse model of Alzheimer\u2019s disease","volume":"161","author":"Woolley","year":"2005","journal-title":"Behav. Brain Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"jcs255752","DOI":"10.1242\/jcs.255752","article-title":"Upregulation of APP endocytosis by neuronal aging drives amyloid-dependent synapse loss","volume":"134","author":"Burrinha","year":"2021","journal-title":"J. Cell Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.neuroscience.2014.11.051","article-title":"Seizures in Alzheimer\u2019s disease","volume":"286","author":"Born","year":"2015","journal-title":"Neuroscience"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/2\/238\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:14:54Z","timestamp":1760364894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/2\/238"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,11]]},"references-count":102,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["cells11020238"],"URL":"https:\/\/doi.org\/10.3390\/cells11020238","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,11]]}}}