Restricted accessResearch articleFirst published online 2025-11
Sex-dependent effect of amyloidosis on functional network ‘hub’ topology is associated with downregulated neuronal gene signatures in the APP swe /PSEN1dE9 double transgenic mouse
Extracellular amyloid-β (Aβ) impairs brain-wide functional connectivity, although mechanisms linking Aβ to broader functional network connectivity remain elusive.
Objective
Here, we evaluated the effect of Aβ on fear memory and functional connectome measures in mice.
Methods
Middle-aged (9–11 months of age) double transgenic APP-PS1 mice and age and sex-matched controls were evaluated on a fear conditioning protocol and then imaged at 11.1 Tesla. Brains were harvested and processed for analysis of Aβ plaques and Iba1 immunolabeling in cortex, hippocampus, and basolateral amygdala. Additional RNA sequencing data from separate age, strain, and sex matched mice were analyzed for differentially expressed genes (DEGs) and weighted gene co-expression networks.
Results
In both male and female mice, we observed increased functional connectivity in a dorsal striatal/amygdala network due to Aβ. Increased functional connectivity within this network was matched by increases in AβPP gene expression, Aβ and Iba1 immunolabeling, and an upregulated cluster of DEGs involved in the immune response. Conversely, the network measure representing node ‘hubness’, eigenvector centrality, was increased in prefrontal cortical brain regions, but only in female APP-PS1 mice. This female specific-effect of amyloid was associated with downregulation of a cluster of DEGs involved in cortical and striatal GABA transmission, anxiogenic responses, and motor activity, in female APP-PS1 mice, but not males.
Conclusions
Our results contribute to a growing literature linking between Aβ, immune activation and functional network connectivity. Furthermore, they reveal effects of Aβ on gene expression patterns in female mice that may contribute to amyloidosis-induced dysregulation of non-cognitive circuitry.
HendriksSPeetoomKBakkerC, et al.Global prevalence of young-onset dementia: a systematic review and meta-analysis. JAMA Neurol2021; 78: 1080–1090.
3.
D'ArgenioVSarnataroD. New insights into the molecular bases of familial Alzheimer's disease. J Pers Med2020; 10: 26.
4.
GuerreiroRJGustafsonDRHardyJ. The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE. Neurobiol Aging2012; 33: 437–456.
5.
MitewSKirkcaldieMTDicksonTC, et al.Altered synapses and gliotransmission in Alzheimer's disease and AD model mice. Neurobiol Aging2013; 34: 2341–2351.
6.
FuhrerTEPalpagamaTHWaldvogelHJ, et al.Impaired expression of GABA transporters in the human Alzheimer's disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus. Neuroscience2017; 351: 108–118.
7.
Dominguez-AlvaroMMontero-CrespoMBlazquez-LlorcaL, et al.Three-dimensional analysis of synapses in the transentorhinal cortex of Alzheimer's disease patients. Acta Neuropathol Commun2018; 6: 20.
8.
KurucuHColom-CadenaMDaviesC, et al.Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease. Eur J Neurol2022; 29: 1311–1323.
9.
Garcia-MarinVBlazquez-LlorcaLRodriguezJR, et al.Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques. Front Neuroanat2009; 3: 28.
10.
VerretLMannEOHangGB, et al.Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell2012; 149: 708–721.
BucknerRLSepulcreJTalukdarT, et al.Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J Neurosci2009; 29: 1860–1873.
13.
AdriaanseSMBinnewijzendMAOssenkoppeleR, et al.Widespread disruption of functional brain organization in early-onset Alzheimer's disease. PLoS One2014; 9: e102995.
14.
CanuEAgostaFMandic-StojmenovicG, et al.Multiparametric MRI to distinguish early onset Alzheimer's disease and behavioural variant of frontotemporal dementia. Neuroimage Clin2017; 15: 428–438.
15.
FilippiMBasaiaSCanuE, et al.Brain network connectivity differs in early-onset neurodegenerative dementia. Neurology2017; 89: 1764–1772.
16.
ZhouJLiKLuoX, et al.Distinct impaired patterns of intrinsic functional network centrality in patients with early- and late-onset Alzheimer's disease. Brain Imaging Behav2021; 15: 2661–2670.
17.
BinnewijzendMAAdriaanseSMVan der FlierWM, et al.Brain network alterations in Alzheimer's disease measured by eigenvector centrality in fMRI are related to cognition and CSF biomarkers. Hum Brain Mapp2014; 35: 2383–2393.
18.
IngalaSTomassenJCollijLE, et al.Amyloid-driven disruption of default mode network connectivity in cognitively healthy individuals. Brain Commun2021; 3: fcab201.
19.
ZhangXZengQWangY, et al.Alteration of functional connectivity network in population of objectively-defined subtle cognitive decline. Brain Commun2024; 6: fcae033.
20.
SkourasS. Eigenvector centrality and its variability over time are promising indicators of alterations in brain function due to early amyloid deposition. Brain Commun2023; 5: fcad104.
21.
SkourasSFalconCTucholkaA, et al.Mechanisms of functional compensation, delineated by eigenvector centrality mapping, across the pathophysiological continuum of Alzheimer's disease. Neuroimage Clin2019; 22: 101777.
22.
LorenziniLIngalaSCollijLE, et al.Eigenvector centrality dynamics are related to Alzheimer's disease pathological changes in non-demented individuals. Brain Commun2023; 5: fcad088.
23.
ZuoXNEhmkeRMennesM, et al.Network centrality in the human functional connectome. Cereb Cortex2012; 22: 1862–1875.
24.
PiniLGeroldiCGalluzziS, et al.Age at onset reveals different functional connectivity abnormalities in prodromal Alzheimer's disease. Brain Imaging Behav2020; 14: 2594–2605.
CochranJNMcKinleyECCochranM, et al.Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles. Cold Spring Harb Mol Case Stud2019; 5: a003491.
27.
EissmanJMDumitrescuLMahoneyER, et al.Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease. Brain2022; 145: 2541–2554.
28.
ShahDJonckersEPraetJ, et al.Resting state FMRI reveals diminished functional connectivity in a mouse model of amyloidosis. PLoS One2013; 8: e84241.
29.
ParentMJZimmerERShinM, et al.Multimodal imaging in rat model recapitulates Alzheimer's disease biomarkers abnormalities. J Neurosci2017; 37: 12263–12271.
30.
GrandjeanJDerungsRKulicL, et al.Complex interplay between brain function and structure during cerebral amyloidosis in APP transgenic mouse strains revealed by multi-parametric MRI comparison. Neuroimage2016; 134: 1–11.
31.
GrandjeanJSchroeterAHeP, et al.Early alterations in functional connectivity and white matter structure in a transgenic mouse model of cerebral amyloidosis. J Neurosci2014; 34: 13780–13789.
32.
JankowskyJLFadaleDJAndersonJ, et al.Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet2004; 13: 159–170.
33.
KarunakaranS. Early beta adrenoceptor dependent time window for fear memory persistence in APPswe/PS1dE9 mice. Sci Rep2021; 11: 870.
34.
JanusCFloresAYXuG, et al.Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains. Neurobiol Aging2015; 36: 2519–2532.
35.
NeunerSMHeuerSEHuentelmanMJ, et al.Harnessing genetic complexity to enhance translatability of Alzheimer's disease mouse models: a path toward precision medicine. Neuron2019; 101: 399–411.e395.
36.
FeboMMaharRRodriguezNA, et al.Age-related differences in affective behaviors in mice: possible role of prefrontal cortical-hippocampal functional connectivity and metabolomic profiles. Front Aging Neurosci2024; 16: 1356086.
37.
Colon-PerezLMIbanezKRSuarezM, et al.Neurite orientation dispersion and density imaging reveals white matter and hippocampal microstructure changes produced by Interleukin-6 in the TgCRND8 mouse model of amyloidosis. Neuroimage2019; 202: 116138.
38.
KotlarzPNinoJCFeboM. Connectomic analysis of Alzheimer's disease using percolation theory. Netw Neurosci2022; 6: 213–233.
39.
SakthivelRCriado-MarreroMBarrosoD, et al.Fixed time-point analysis reveals repetitive mild traumatic brain injury effects on resting state functional magnetic resonance imaging connectivity and neuro-spatial protein profiles. J Neurotrauma2023; 40: 2037–2049.
40.
SadakaAHCanuelJFeboM, et al.Effects of inhaled cannabis high in Delta9-THC or CBD on the aging brain: a translational MRI and behavioral study. Front Aging Neurosci2023; 15: 1055433.
41.
CoxRW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res1996; 29: 162–173.
42.
JenkinsonMBannisterPBradyM, et al.Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage2002; 17: 825–841.
43.
KleinAAnderssonJArdekaniBA, et al.Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. Neuroimage2009; 46: 786–802.
44.
YushkevichPAPivenJHazlettHC, et al.User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage2006; 31: 1116–1128.
45.
WangQDingSLLiY, et al.The Allen mouse brain common coordinate framework: a 3D reference atlas. Cell2020; 181: 936–953.e920.
46.
PompilusMColon-PerezLMGrudnyMM, et al.Contextual experience modifies functional connectome indices of topological strength and efficiency. Sci Rep2020; 10: 19843.
47.
YangZZhuTPompilusM, et al.Compensatory functional connectome changes in a rat model of traumatic brain injury. Brain Commun2021; 3: fcab244.
48.
XiaMWangJHeY. Brainnet Viewer: a network visualization tool for human brain connectomics. PLoS One2013; 8: e68910.
49.
RubinovMSpornsO. Complex network measures of brain connectivity: uses and interpretations. Neuroimage2010; 52: 1059–1069.
50.
WangYGhumareEVandenbergheR, et al.Comparison of different generalizations of clustering coefficient and local efficiency for weighted undirected graphs. Neural Comput2017; 29: 313–331.
51.
BlondelVDGuillaumeJ-PLambiotteR, et al.Fast unfolding of communities in large networks. J Stat Mech2008; 2008: 2–12.
52.
NewmanME. Assortative mixing in networks. Phys Rev Lett2002; 89: 208701.
53.
MorganMPagesHObenchainV, et al.Rsamtools: Binary alignment (BAM), FASTA, variant call (BCF), and tabix file import. doi:10.18129/B9.bioc.Rsamtools
54.
LawrenceMHuberWPagesH, et al.Software for computing and annotating genomic ranges. PLoS Comput Biol2013; 9: e1003118.
55.
LoveMIHuberWAndersS. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol2014; 15: 550.
56.
ZhangYChenKSloanSA, et al.An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci2014; 34: 11929–11947.
57.
LangfelderPHorvathS. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics2008; 9: 559.
58.
LangfelderPHorvathS. Fast R functions for robust correlations and hierarchical clustering. J Stat Softw2012; 46: i11.
59.
BeckmannCFSmithSM. Probabilistic independent component analysis for functional magnetic resonance imaging. IEEE Trans Med Imaging2004; 23: 137–152.
60.
HyvarinenA. Fast and robust fixed-point algorithms for independent component analysis. IEEE Trans Neural Netw1999; 10: 626–634.
61.
BukhariQSchroeterAColeDM, et al.Resting state fMRI in mice reveals anesthesia specific signatures of brain functional networks and their interactions. Front Neural Circuits2017; 11: 5.
62.
JonckersEVan AudekerkeJDe VisscherG, et al.Functional connectivity fMRI of the rodent brain: comparison of functional connectivity networks in rat and mouse. PLoS One2011; 6: e18876.
63.
SforazziniFSchwarzAJGalbuseraA, et al.Distributed BOLD and CBV-weighted resting-state networks in the mouse brain. Neuroimage2014; 87: 403–415.
64.
McFarlandKNCeballosCRosarioA, et al.Microglia show differential transcriptomic response to Abeta peptide aggregates ex vivo and in vivo. Life Sci Alliance2021; 4: e202101108.
65.
BuscheMAWegmannSDujardinS, et al.Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimer models in vivo. Nat Neurosci2019; 22: 57–64.
66.
Calvo-Flores GuzmanBKimSChawdharyB, et al.Amyloid-beta(1-42) -induced increase in GABAergic tonic conductance in mouse hippocampal CA1 pyramidal cells. Molecules2020; 25: 693.
67.
LauterbornJCScadutoPCoxCD, et al.Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer's disease. Nat Commun2021; 12: 2603.
68.
PetracheALRajulawallaAShiA, et al.Aberrant excitatory-inhibitory synaptic mechanisms in entorhinal cortex microcircuits during the pathogenesis of Alzheimer's disease. Cereb Cortex2019; 29: 1834–1850.
69.
ShahDDeleyeSVerhoyeM, et al.Resting-state functional MRI and [18F]-FDG PET demonstrate differences in neuronal activity between commonly used mouse strains. Neuroimage2016; 125: 571–577.
70.
GrandjeanJSchroeterABatataI, et al.Optimization of anesthesia protocol for resting-state fMRI in mice based on differential effects of anesthetics on functional connectivity patterns. Neuroimage2014; 102: 838–847.
71.
WhitesellJDBuckleyARKnoxJE, et al.Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer's disease. J Comp Neurol2019; 527: 2122–2145.
72.
GrandjeanJZerbiVBalstersJH, et al.Structural basis of large-scale functional connectivity in the mouse. J Neurosci2017; 37: 8092–8101.
73.
ArszovszkiABorhegyiZKlausbergerT. Three axonal projection routes of individual pyramidal cells in the ventral CA1 hippocampus. Front Neuroanat2014; 8: 53.
74.
OrsiniCAKimJHKnapskaE, et al.Hippocampal and prefrontal projections to the basal amygdala mediate contextual regulation of fear after extinction. J Neurosci2011; 31: 17269–17277.
75.
IshikawaANakamuraS. Ventral hippocampal neurons project axons simultaneously to the medial prefrontal cortex and amygdala in the rat. J Neurophysiol2006; 96: 2134–2138.
76.
SwansonLWKohlerC. Anatomical evidence for direct projections from the entorhinal area to the entire cortical mantle in the rat. J Neurosci1986; 6: 3010–3023.
77.
ThierryAMGioanniYDegenetaisE, et al.Hippocampo-prefrontal cortex pathway: anatomical and electrophysiological characteristics. Hippocampus2000; 10: 411–419.
LiuDLuHSteinE, et al.Brain regional synchronous activity predicts tauopathy in 3xTgAD mice. Neurobiol Aging2018; 70: 160–169.
80.
GiorgioJAdamsJNMaassA, et al.Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation. Neuron2024; 112: 676–686.e674.
81.
HuWPanDWangY, et al.PET Imaging for dynamically monitoring neuroinflammation in APP/PS1 mouse model using [(18)F]DPA714. Front Neurosci2020; 14: 810.
82.
GarlandEFDennettOLauLC, et al.The mitochondrial protein TSPO in Alzheimer's disease: relation to the severity of AD pathology and the neuroinflammatory environment. J Neuroinflammation2023; 20: 186.
83.
GiulianDLiJBartelS, et al.Cell surface morphology identifies microglia as a distinct class of mononuclear phagocyte. J Neurosci1995; 15: 7712–7726.
84.
WakeHMoorhouseAJJinnoS, et al.Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci2009; 29: 3974–3980.
85.
ZhanYPaolicelliRCSforazziniF, et al.Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci2014; 17: 400–406.
86.
TremblayMELoweryRLMajewskaAK. Microglial interactions with synapses are modulated by visual experience. PLoS Biol2010; 8: e1000527.
87.
TremblayMEMajewskaAK. A role for microglia in synaptic plasticity?Commun Integr Biol2011; 4: 220–222.
88.
BolosMPereaJRTerreros-RoncalJ, et al.Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons. Brain Behav Immun2018; 68: 76–89.
89.
LitumaPJWooEO'HaraBF, et al.Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1. Proc Natl Acad Sci U S A2021; 118: e2115539118.
90.
SuralaMSoso-ZdravkovicLMunroD, et al.Lifelong absence of microglia alters hippocampal glutamatergic networks but not synapse and spine density. EMBO Rep2024; 25: 2348–2374.
91.
LalondeRKimHDMaxwellJA, et al.Exploratory activity and spatial learning in 12-month-old APP(695)SWE/co+PS1/DeltaE9 mice with amyloid plaques. Neurosci Lett2005; 390: 87–92.
92.
KilgoreMMillerCAFassDM, et al.Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology2010; 35: 870–880.
93.
HeddenTVan DijkKRBeckerJA, et al.Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J Neurosci2009; 29: 12686–12694.
94.
LimHKNebesRSnitzB, et al.Regional amyloid burden and intrinsic connectivity networks in cognitively normal elderly subjects. Brain2014; 137: 3327–3338.
95.
HulshofLAFrajmundLAvan NuijsD, et al.Both male and female APPswe/PSEN1dE9 mice are impaired in spatial memory and cognitive flexibility at 9 months of age. Neurobiol Aging2022; 113: 28–38.
96.
KimHYKimHVJoS, et al.EPPS Rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-beta oligomers and plaques. Nat Commun2015; 6: 8997.
97.
O'LearyTPHussinATGunnRK, et al.Locomotor activity, emotionality, sensori-motor gating, learning and memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease. Brain Res Bull2018; 140: 347–354.
98.
KnafoSVeneroCMerino-SerraisP, et al.Morphological alterations to neurons of the amygdala and impaired fear conditioning in a transgenic mouse model of Alzheimer's disease. J Pathol2009; 219: 41–51.
99.
KommaddiRPDasDKarunakaranS, et al.Abeta mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease. J Neurosci2018; 38: 1085–1099.
100.
MelnikovaTParkDBeckerL, et al.Sex-related dimorphism in dentate gyrus atrophy and behavioral phenotypes in an inducible tTa:APPsi transgenic model of Alzheimer's disease. Neurobiol Dis2016; 96: 171–185.
101.
MortbergMAZhaoHTReidenbachAG, et al.Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS. JCI Insight2022; 7: e156532.
102.
XuJBurgoynePSArnoldAP. Sex differences in sex chromosome gene expression in mouse brain. Hum Mol Genet2002; 11: 1409–1419.
103.
QiuTLuoXShenZ, et al.Disrupted brain network in progressive mild cognitive impairment measured by eigenvector centrality mapping is linked to cognition and cerebrospinal fluid biomarkers. J Alzheimers Dis2016; 54: 1483–1493.
104.
StoneDJWalshJBenesFM. Localization of cells preferentially expressing GAD(67) with negligible GAD(65) transcripts in the rat hippocampus. A double in situ hybridization study. Brain Res Mol Brain Res1999; 71: 201–209.
105.
LiQSSunYWangT. Epigenome-wide association study of Alzheimer's disease replicates 22 differentially methylated positions and 30 differentially methylated regions. Clin Epigenetics2020; 12: 149.
106.
HalderSKSasakiKUedaH. Ggamma7-specific prothymosin alpha deletion causes stress- and age-dependent motor dysfunction and anxiety. Biochem Biophys Res Commun2020; 522: 264–269.
107.
BrunoriGPelletierOBStaufferAM, et al.Selective manipulation of G-protein gamma(7) subunit in mice provides new insights into striatal control of motor behavior. J Neurosci2021; 41: 9065–9081.
108.
ChoiMRHanJSJinYB, et al.Differential expression of microRNAs in the hippocampi of male and female rodents after chronic alcohol administration. Biol Sex Differ2020; 11: 65.
109.
MaYReyes-DumeyerDPirizA, et al.Multi-omics characterization of epigenetic and genetic risk of Alzheimer disease in autopsied brains from two ethnic groups. medRxiv 2024; DOI:10.1101/2024.02.12.24302533 [Preprint]. Posted February 14, 2024.
110.
ReedTMRepaskeDRSnyderGL, et al.Phosphodiesterase 1B knock-out mice exhibit exaggerated locomotor hyperactivity and DARPP-32 phosphorylation in response to dopamine agonists and display impaired spatial learning. J Neurosci2002; 22: 5188–5197.
111.
HebbALRobertsonHADenovan-WrightEM. Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington's disease transgenic mice prior to the onset of motor symptoms. Neuroscience2004; 123: 967–981.
112.
HufgardJRWilliamsMTVorheesCV. Phosphodiesterase-1b deletion confers depression-like behavioral resistance separate from stress-related effects in mice. Genes Brain Behav2017; 16: 756–767.
113.
TeagueCDMarkovicTZhouX, et al.Circuit-wide gene network analysis reveals sex-specific roles for phosphodiesterase 1b in cocaine addiction. J Neurosci2024; 44: e1327232024.
114.
OuimetCCGreengardP. Distribution of DARPP-32 in the basal ganglia: an electron microscopic study. J Neurocytol1990; 19: 39–52.
115.
ZhouLNazarianASunWL, et al.Basal and cocaine-induced sex differences in the DARPP-32-mediated signaling pathway. Psychopharmacology (Berl)2009; 203: 175–183.
116.
WeinerJSunWLZhouL, et al.PKA-mediated responses in females’ estrous cycle affect cocaine-induced responses in dopamine-mediated intracellular cascades. Neuroscience2009; 161: 865–876.
117.
StroppoloATianCGuineaB, et al.17beta-Estradiol Promotes striatal medium size spiny neuronal maturation in vitro. Neuroendocrinology2004; 79: 259–267.
118.
WangJTanilaHPuolivaliJ, et al.Gender differences in the amount and deposition of amyloidbeta in APPswe and PS1 double transgenic mice. Neurobiol Dis2003; 14: 318–327.
119.
WuJFuBLeiH, et al.Gender differences of peripheral plasma and liver metabolic profiling in APP/PS1 transgenic AD mice. Neuroscience2016; 332: 160–169.
120.
LeeJYColeTBPalmiterRD, et al.Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci U S A2002; 99: 7705–7710.
121.
Hirata-FukaeCLiHFHoeHS, et al.Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res2008; 1216: 92–103.
122.
ZhengHXuHUljonSN, et al.Modulation of A(beta) peptides by estrogen in mouse models. J Neurochem2002; 80: 191–196.
123.
CarrollJCRosarioERChangL, et al.Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci2007; 27: 13357–13365.
124.
CuiJAit-GhezalaGSambamurtiK, et al.Sex-specific regulation of beta-secretase: a novel estrogen response element (ERE)-dependent mechanism in Alzheimer's disease. J Neurosci2022; 42: 1154–1165.
125.
Vargas-SoriaMRamos-RodriguezJJDel MarcoA, et al.Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer s disease and type two diabetes. Fluids Barriers CNS2022; 19: 88.
126.
BuXLXiangYJinWS, et al.Blood-derived amyloid-beta protein induces Alzheimer's disease pathologies. Mol Psychiatry2018; 23: 1948–1956.
127.
Garcia-AllozaMPradaCLattaruloC, et al.Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice. J Neurochem2009; 109: 1636–1647.
128.
Garcia-AllozaMRobbinsEMZhang-NunesSX, et al.Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis2006; 24: 516–524.
129.
AllenEADamarajuEPlisSM, et al.Tracking whole-brain connectivity dynamics in the resting state. Cereb Cortex2014; 24: 663–676.
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