Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice

Larramona-Arcas, Raquel; González-Arias, Candela; Perea, Gertrudis; Gutiérrez, Antonia; Vitorica, Javier; García-Barrera, Tamara; Gómez-Ariza, José Luis; Pascua-Maestro, Raquel; Ganfornina, María Dolores; Kara, Eleanna; Hudry, Eloise; Martinez-Vicente, Marta; Vila, Miquel; Galea, Elena; Masgrau, Roser

doi:10.1186/s13024-020-00382-8

Cited by 56Alzheimer's disease research and treatmentsCalcium signaling and nucleotide metabolismNeuroscience and Neuropharmacology Research

Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice

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Larramona-Arcas, Raquel, González-Arias, Candela, Perea, Gertrudis, Gutiérrez, Antonia, Vitorica, Javier, García-Barrera, Tamara, Gómez-Ariza, José Luis, Pascua-Maestro, Raquel +7 more·2020·Molecular Neurodegeneration

DOI 10.1186/s13024-020-00382-8PMC PMC7285605

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Abstract

Background: The apolipoprotein E (APOE) gene exists in three isoforms in humans: APOE2, APOE3 and APOE4. APOE4 causes structural and functional alterations in normal brains, and is the strongest genetic risk factor of the sporadic form of Alzheimer’s disease (LOAD). Research on APOE4 has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-β and Tau pathology. The impact of APOE4 on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca 2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca 2+ channels, we determined whether APOE4 dysregulates Ca 2+signaling in astrocytes. Methods: Ca 2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca 2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca 2+ fluxes were examined with pharmacological tools and Ca 2+ probes. APOE3 and APOE4 expression was manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes were also performed. Results: We found potentiation of ATP-elicited Ca 2+responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca 2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca 2+ handling in lysosomal-enriched acidic stores, and is reversed by the expression of APOE3, but not of APOE4, pointing to loss of function due to APOE4 malfunction. Moreover, immortalized APOE4 astrocytes are refractory to control of Ca 2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes. Conclusions: Immortalized APOE4 versus APOE3 astrocytes present: increased Ca 2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca 2+ responses upon changes in extracellular lipids. Ca 2+ hyperactivity associated with APOE4 is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aβ and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on APOE allele, sex and lipids, and supports lysosome-targeted therapies to rescue APOE4 phenotypes in LOAD.

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Ca hyperactivity associated with ApoE4 is found in astrocytes from targeted replacement mice.
“Ca hyperactivity associated with ApoE4 is found in astrocytes from targeted replacement mice [52].”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [52]
The Discussion reports Ca2+ hyperactivity in astrocytes from APOE4 targeted replacement male mice, but not females. The claim omits that sex-specific limitation. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Astrocytes expressing ApoE4 exhibit higher cytosolic levels of Ca2+, mainly through ER IP3R-mediated release.
“astrocytes expressing ApoE4 exhibit higher cytosolic levels of Ca2+, mainly through ER inositol 1,4,5-trisphosphate receptor (IP3R)-mediated release [57].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [57]
The Results report greater stimulus-evoked cytosolic Ca2+ responses in APOE4 than APOE3 astrocytes, but not generally higher resting levels; another Results passage reports lower basal Ca2+ in APOE4 cells. The proposed main mechanism is also wrong: the Results say ER release is only slightly increased and cannot alone explain the larger responses, while the Discussion identifies increased release from acidic stores as the key difference (pages not available in our copy). (LLM, conf=0.90)
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Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology.
Wang, C., Wilson, W. A., Moore, S. D., Mace, B. E., Maeda, N., Schmechel, D. E., & Sullivan, P. M. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.10.013 · Cited by 138 · see citing works
Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease
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Impaired Autophagy in APOE4 Astrocytes
Simonovitch, S., Schmukler, E., Bespalko, A., Iram, T., Frenkel, D., Holtzman, D. M., Masliah, E., Michaelson, D. M., & Pinkas-Kramarski, R. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-151101 · Cited by 136 · see citing works
Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortexPreprint
Rodriguez, G. A., Burns, M. P., Weeber, E. J., & Rebeck, G. W. (2013) · Learning & Memory · doi:10.1101/lm.030031.112 · Cited by 134 · see citing works
Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis
Liao, F., Hori, Y., Hudry, E., Bauer, A. Q., Jiang, H., Mahan, T. E., Lefton, K. B., Zhang, T. J., Dearborn, J. T., Kim, J., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.0646-14.2014 · Cited by 128 · see citing works
Self-citation
Apolipoprotein E4 (1–272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells
Nakamura, T., Watanabe, A., Fujino, T., Hosono, T., & Michikawa, M. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-35 · Cited by 124 · see citing works
A primer of NAADP-mediated Ca2+ signalling: From sea urchin eggs to mammalian cells
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Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Regulates Autophagy in Cultured Astrocytes
Pereira, G. J. S., Hirata, H., Fimia, G. M., do Carmo, L. G., Bincoletto, C., Han, S. W., Stilhano, R. S., Ureshino, R. P., Bloor-Young, D., Churchill, G. C., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.c110.216580 · Cited by 118 · see citing works
Metabolomic study of lipids in serum for biomarker discovery in Alzheimer's disease using direct infusion mass spectrometry
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Apolipoprotein E4 genotype compromises brain exosome production
Peng, K. Y., Pérez-González, R., Alldred, M. J., Goulbourne, C. N., Morales-Corraliza, J., Saito, M., Saito, M., Ginsberg, S. D., Mathews, P. M., & Levy, E. (2019) · Brain · doi:10.1093/brain/awy289 · Cited by 109 · see citing works
Ca2+/H+ exchange by acidic organelles regulates cell migration in vivo
Melchionda, M., Pittman, J. K., Mayor, R., & Patel, S. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201510019 · Cited by 102 · see citing works
Regulation of Store-Operated Calcium Entry by Calcium-Independent Phospholipase A2in Rat Cerebellar Astrocytes
Singaravelu, K., Lohr, C., & Deitmer, J. W. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2604-06.2006 · Cited by 94 · see citing works
Absolute 10-year risk of dementia by age, sex and APOE genotype: a population-based cohort study
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Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells
Sun, Y., Sukumaran, P., Varma, A., Derry, S., Sahmoun, A. E., & Singh, B. B. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.04.019 · Cited by 90 · see citing works
Evolution of acidic Ca2+ stores and their resident Ca2+-permeable channels
Patel, S., & Cai, X. (2014) · Cell Calcium · doi:10.1016/j.ceca.2014.12.005 · Cited by 87 · see citing works
A roadmap to integrate astrocytes into Systems Neuroscience
Kastanenka, K. V., Moreno‐Bote, R., Pittà, M. D., Perea, G., Eraso‐Pichot, A., Masgrau, R., Poskanzer, K. E., & Galea, E. (2019) · Glia · doi:10.1002/glia.23632 · Cited by 83 · see citing works
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Protecting cells by protecting their vulnerable lysosomes: Identification of a new mechanism for preserving lysosomal functional integrity upon oxidative stress
Pascua‐Maestro, R., Diez‐Hermano, S., Lillo, C., Ganfornina, M. D., & Sánchez, D. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006603 · Cited by 78 · see citing works
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Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers
Perkins, M., Wolf, A. B., Chavira, B., Shonebarger, D., Meckel, J. P., Leung, L., Ballina, L. E., Ly, S., Saini, A., Jones, T. B., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151205 · Cited by 74 · see citing works
Free Cholesterol Alters Lipid Raft Structure and Function Regulating Neutrophil Ca2+ Entry and Respiratory Burst: Correlations with Calcium Channel Raft Trafficking
Kannan, K. B., Barlos, D., & Hauser, C. J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.8.5253 · Cited by 69 · see citing works
The endo-lysosomal system as an NAADP-sensitive acidic Ca2+ store: Role for the two-pore channels
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Sex differences in hypothalamic astrocyte response to estradiol stimulation
Kuo, J., Hamid, N., Bondar, G., Dewing, P., Clarkson, J., & Micevych, P. E. (2010) · Biology of Sex Differences · doi:10.1186/2042-6410-1-7 · Cited by 64 · see citing works
ApoE4-associated phospholipid dysregulation contributes to development of Tau hyper-phosphorylation after traumatic brain injury
Cao, J., Gaamouch, F. E., Meabon, J. S., Meeker, K. D., Zhu, L., Zhong, M. B., Bendik, J., Elder, G., Jing, P., Xia, J., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-11654-7 · Cited by 62 · see citing works
Astrocytes express functional TRPV2 ion channels
Shibasaki, K., Ishizaki, Y., & Mandadi, S. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.10.046 · Cited by 60 · see citing works
Apolipoprotein E ε4 Allele Is Associated with Vascular Dementia
Baum, L., Lam, L. C. W., Kwok, T., Lee, J., Chiu, H. F. K., Mok, V. C. T., Wong, A., Chen, X., Cheung, W. S., Pang, C. P., et al. (2006) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000095246 · Cited by 57 · see citing works
Metabolic disturbances of a high-fat diet are dependent on APOE genotype and sex.
Jones, N. S., Watson, K. Q., & Rebeck, G. W. (2019) · eneuro · doi:10.1523/eneuro.0267-19.2019 · Cited by 54 · see citing works
Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice
Shang, Y., Mishra, A., Wang, T., Wang, Y., Desai, M. K., Chen, S., Mao, Z., Do, L., Bernstein, A. S., Trouard, T. P., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0225392 · Cited by 36 · see citing works
Risk communication in times of crisis
Böl, G. (2015) · EMBO Reports · doi:10.15252/embr.201541678 · Cited by 35 · see citing works
Apolipoprotein E4 causes early olfactory network abnormalities and short-term olfactory memory impairments
Peng, K. Y., Mathews, P. M., Levy, E., & Wilson, D. A. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.12.004 · Cited by 34 · see citing works
Discovery and Confirmation of Diagnostic Serum Lipid Biomarkers for Alzheimer’s Disease Using Direct Infusion Mass Spectrometry
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NAADP mediates ATP-induced Ca2+ signals in astrocytes
Barceló-Torns, M., Lewis, A. M., Gubern, A., Barneda, D., Bloor-Young, D., Picatoste, F., Churchill, G. C., Claro, E., & Masgrau, R. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.062 · Cited by 30 · see citing works
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Apolipoprotein E and Sex Bias in Cerebrovascular Aging of Men and Mice
Finch, C. E., & Shams, S. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.07.002 · Cited by 29 · see citing works
NAADP/TPC2/Ca2+Signaling Inhibits Autophagy
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Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice
Klein, R. C., Acheson, S. K., Mace, B. E., Sullivan, P. M., & Moore, S. D. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.02.019 · Cited by 28 · see citing works
Voltage-sensing phosphatase reveals temporal regulation of TRPC3/C6/C7 channels by membrane phosphoinositides
Itsuki, K., Imai, Y., Okamura, Y., Abe, K., Inoue, R., & Mori, M. X. (2012) · Channels · doi:10.4161/chan.20883 · Cited by 22 · see citing works
A gene−brain−cognition pathway for the effect of an Alzheimer׳s risk gene on working memory in young adults
Stevens, B. W., DiBattista, A. M., Rebeck, G. W., & Green, A. E. (2014) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2014.06.021 · Cited by 20 · see citing works
In Vivo Two Photon Imaging of Astrocytic Structure and Function in Alzheimer’s Disease
Kelly, P., Hudry, E., Hou, S. S., & Bacskai, B. J. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00219 · Cited by 19 · see citing works
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Very Low-Density Lipoproteins of Metabolic Syndrome Modulates STIM1, Suppresses Store-Operated Calcium Entry, and Deranges Myofilament Proteins in Atrial Myocytes
Shiou, Y.-L., Lin, H.-T., Ke, L., Wu, B., Shin, S., Chen, C., Tsai, W., Chu, C., & Lee, H. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8060881 · Cited by 17 · see citing works
Reduced membrane cholesterol limits pulmonary endothelial Ca2+entry after chronic hypoxia
Zhang, B., Naik, J. S., Jernigan, N. L., Walker, B. R., & Resta, T. C. (2017) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00097.2017 · Cited by 15 · see citing works
Time sensing by NAADP receptors
Churamani, D., Dickinson, G. D., Ziegler, M., & Patel, S. (2006) · Biochemical Journal · doi:10.1042/bj20060179 · Cited by 14 · see citing works
CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor
Eraso‐Pichot, A., Larramona‐Arcas, R., Orri, E. V., Villalonga, R., Pardo, L., Galea, E., & Masgrau, R. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2397-5 · Cited by 12 · see citing works
Self-citation
Lipid interactions with ion channels
Lee, A. J. (2006) · Future Lipidology · doi:10.2217/17460875.1.1.103 · Cited by 9 · see citing works

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Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders
Brandebura, A. N., Paumier, A., Onur, T. S., & Allen, N. J. (2023) · Nature Reviews Neuroscience · doi:10.1038/s41583-022-00641-1 · Cited by 427 · see citing works
APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
Lipid-accumulated reactive astrocytes promote disease progression in epilepsy
Chen, Z.-P., Wang, S., Zhao, X., Fang, W., Wang, Z., Ye, H., Wang, M.-J., Ke, L., Huang, T., Lv, P., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01288-6 · Cited by 214 · see citing works
Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies
Pires, M., & Rego, A. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010778 · Cited by 157 · see citing works
Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer’s disease brains
Sharoar, M. G., Palko, S., Ge, Y., Saido, T. C., & Yan, R. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00464-1 · Cited by 78 · see citing works
Astroglial activation: Current concepts and future directions
Edison, P. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13678 · Cited by 64 · see citing works
Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction
Bandyopadhyay, S. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.653334 · Cited by 62 · see citing works
Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
Miranda, A. M., Ashok, A., Chan, R. B., Zhou, B., Xu, Y., McIntire, L. B., Area-Gomez, E., Di Paolo, G., Duff, K. E., Oliveira, T. G., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01881-6 · Cited by 60 · see citing works
“Also, we previously reported increased expression of several V-type ATPase subunits [33], possibly in response to altered lysosomal pH and membrane composition [68, 69].”
Background
Therapeutic Strategies to Target Calcium Dysregulation in Alzheimer’s Disease
Calvo-Rodríguez, M., Kharitonova, E. K., & Bacskai, B. J. (2020) · Cells · doi:10.3390/cells9112513 · Cited by 59 · see citing works
Astrocytic Calcium and cAMP in Neurodegenerative Diseases
Sobolczyk, M., & Boczek, T. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.889939 · Cited by 50 · see citing works
Physiological and Pathological Ageing of Astrocytes in the Human Brain
Verkerke, M., Hol, E. M., & Middeldorp, J. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03256-7 · Cited by 49 · see citing works
Revealing cell vulnerability in Alzheimer’s disease by single-cell transcriptomics
Saura, C. A., Deprada-Fernandez, Á., Capilla-López, M. D., & Parra‐Damas, A. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.05.007 · Cited by 46 · see citing works
A multi‐hit hypothesis for an APOE4 ‐dependent pathophysiological state
Steele, O. G., Stuart, A. C., Minkley, L., Shaw, K., Bonnar, O., Anderle, S., Penn, A. C., Rusted, J., Serpell, L., Hall, C., et al. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15685 · Cited by 44 · see citing works
Astrocytic and neuronal apolipoprotein E isoforms differentially affect neuronal excitability
Konings, S. C., Torres-Garcia, L., Martinsson, I., & Gouras, G. K. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.734001 · Cited by 43 · see citing works
APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline
Fang, W., Xiao, N., Zeng, G., Bi, D., Dai, X., Mi, X., Ye, Q., Chen, X., & Zhang, J. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01631-0 · Cited by 42 · see citing works
Astrocytes: The Stars in Neurodegeneration?
Dittlau, K. S., & Freude, K. (2024) · Biomolecules · doi:10.3390/biom14030289 · Cited by 38 · see citing works
Lysosomal acidification impairment in astrocyte-mediated neuroinflammation
Zeng, J., Indajang, J., Pitt, D., & Lo, C. H. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03410-w · Cited by 38 · see citing works
Navigating the metabolic maze: anomalies in fatty acid and cholesterol processes in Alzheimer’s astrocytes
Zhang, X., Chen, C., & Liu, Y. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01430-x · Cited by 32 · see citing works
Factors Influencing Alzheimer’s Disease Risk: Whether and How They are Related to the APOE Genotype
Zhang, R., Xu, X., Yu, H., Xu, X., Wang, M., & Le, W. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-021-00814-5 · Cited by 28 · see citing works
<scp>ApoE4</scp> expression disrupts tau uptake, trafficking, and clearance in astrocytes
Eisenbaum, M., Pearson, A., Ortiz, C., Mullan, M., Crawford, F., Ojo, J., & Bachmeier, C. (2024) · Glia · doi:10.1002/glia.24469 · Cited by 27 · see citing works
Suppression of Wnt/β-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer’s Disease
Macyczko, J. R., Wang, N., Zhao, J., Ren, Y., Lü, W., Ikezu, T. C., Zhao, N., Liu, C., Bu, G., & Li, Y. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03065-1 · Cited by 23 · see citing works
The Association of Essential Metals with APOE Genotype in Alzheimer’s Disease
Leko, M. B., Jurasović, J., Perković, M. N., Španić, E., Sekovanić, A., Orct, T., Lukinović-Škudar, V., Baronica, K. B., Kiđemet‐Piskač, S., Vogrinc, Ž., et al. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210158 · Cited by 21 · see citing works
A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease
Chen, H., Chen, F., Jiang, Y., Zhang, L., Hu, G., Sun, F., Zhang, M., Ji, Y., Chen, Y., Che, G., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.881239 · Cited by 19 · see citing works
APOE4-driven lipid metabolic dysregulation in Alzheimer's disease: Multi-pathway mechanisms and therapeutic perspectives
Zhang, W.-X., Yang, Y.-L., Yu, J., Jia, L., & Huang, H. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152335 · Cited by 17 · see citing works
Astrocytes and Microglia in Alzheimer's Disease: Friends, Foes, or Both?
Sharma, A., Parekh, B. K., Patil, V., Renuka Jyothi, S., Nayak, P. P., Janney, J. B., Singh, G., & Al-Hasnaawei, S. (2025) · Developmental Neurobiology · doi:10.1002/dneu.23015 · Cited by 17 · see citing works
APOE ε4 allele, along with G206D-PSEN1 mutation, alters mitochondrial networks and their degradation in Alzheimer’s disease
Laparra, I. C., Juárez‐Escoto, E., Vicario‐Abejón, C., Moratalla, R., & García‐Sanz, P. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1087072 · Cited by 17 · see citing works
Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases
Jia, H., Ma, L., Liu, J., Gao, M., Liang, X., Zhang, F., Gao, Y., Liu, M., Jiang, W., Wei, M., et al. (2026) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00922-0 · Cited by 16 · see citing works
A Review of APOE Genotype-Dependent Autophagic Flux Regulation in Alzheimer’s Disease
Chen, H., Chen, F., Zhang, M., Chen, Y., Cui, L., & Liang, C. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210602 · Cited by 15 · see citing works
Isoform- and cell-state-specific APOE homeostasis and function
Lindner, K., & Gavin, A.-C. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01470 · Cited by 13 · see citing works
When the Stars Misfire: Astrocytic Dysfunctions in Major Depressive Disorder
González-Arias, C., & Perea, G. (2025) · Neurochemical Research · doi:10.1007/s11064-025-04483-y · Cited by 13 · see citing works
Self-citation
Imaging mitochondrial calcium dynamics in the central nervous system
Serrat, R., Oliveira-Pinto, A., Marsicano, G., & Pouvreau, S. (2022) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2022.109560 · Cited by 13 · see citing works
Excitation–inhibition homeostasis in Alzheimer’s disease: a selective multiscale review of mechanisms, sex differences, and therapeutic opportunities
Burns, A. P., Duran, M. I., Fortel, I., Lazarov, O., Zhan, L., Bendlin, B. B., & Leow, A. (2026) · Neuropsychopharmacology · doi:10.1038/s41386-026-02334-0 · Cited by 11 · see citing works
Optogenetics in Alzheimer’s Disease: Focus on Astrocytes
Mitroshina, Е. V., Kalinina, E. P., & Vedunova, M. V. (2023) · Antioxidants · doi:10.3390/antiox12101856 · Cited by 10 · see citing works
The Contributions of the Endolysosomal Compartment and Autophagy to APOE ɛ4 Allele-Mediated Increase in Alzheimer’s Disease Risk
Asiamah, E. A., Feng, B., Guo, R., Yaxing, X., Du, X., Liu, X., Zhang, J., Cui, H., & Ma, J. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230658 · Cited by 8 · see citing works
APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice
Bonnar, O., Shaw, K., Anderle, S., Grijseels, D. M., Clarke, D., Bell, L., King, S. L., & Hall, C. N. (2023) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x231172842 · Cited by 8 · see citing works
Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer’s disease neuropathology
Arnsten, A. F. T., Perone, I., Wang, M., Yang, S., Uchendu, S., Bolat, D., & Datta, D. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1610350 · Cited by 7 · see citing works
Repetitive Transcranial Magnetic Stimulation for Alzheimer’s Disease Based on Apolipoprotein E Genotyping: Protocol for a Randomized Controlled Study
Wei, N., & Chen, J. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.758765 · Cited by 7 · see citing works
Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System
Passarella, D., Ronci, M., Liberto, V. D., Zuccarini, M., Mudò, G., Porcile, C., Frinchi, M., Iorio, P. D., Ulrich, H., & Russo, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158683 · Cited by 7 · see citing works
Advances in the Study of APOE and Innate Immunity in Alzheimer’s Disease
Li, Y., Chang, J., Chen, X., Liu, J., & Zhao, L. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230179 · Cited by 6 · see citing works
Research progress in the evaluation of glymphatic system function by the DTI-ALPS method.
Wang, S., Sun, S., Liu, H., & Huang, Q. M. (2023) · PubMed Central · doi:10.11817/j.issn.1672-7347.2023.230091 · Cited by 4 · see citing works
Astrovascular decoupling in awake 5×FAD mice is associated with reduced astrocytic calcium
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Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration
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Apoe4 pathology in alzheimer's disease from the perspective of organelle dysfunction in astrocytes
Larramona‐Arcas, R. (2018)
Self-citation
Astrocyte Dysfunction in Alzheimer's Disease: From APOE Genetic Risk to Calcium Signaling.
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Authors: Larramona-Arcas, R., González-Arias, C., Perea, G., Gutiérrez, A., Vitorica, J., García-Barrera, T., Gómez-Ariza, J. L., Pascua-Maestro, R., Ganfornina, M. D., Kara, E., Hudry, E., Martinez-Vicente, M., Vila, M., Galea, E., & Masgrau, R.
Affiliations: Consejo Superior de Investigaciones Científicas (ES)
Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
Universidad de Valladolid (ES)
Harvard University (US)
Institució Catalana de Recerca i Estudis Avançats (ES)
Universitat Autònoma de Barcelona (ES)
Corresponding author: Masgrau, Roser
ORCID: González-Arias, Candela
Perea, Gertrudis
Gutiérrez, Antonia
Ganfornina, María Dolores
Kara, Eleanna
Vila, Miquel
Galea, Elena
Masgrau, Roser
Venue: Molecular Neurodegeneration
Publisher: Springer Science and Business Media LLC
Published: 2020-06-09
Volume: 15
Issue: 1
Pages: 35-35
ISSN: 1750-1326 (ISSN-L)
DOI: 10.1186/s13024-020-00382-8
PMC: PMC7285605
OpenAlex: W3034140617
Cited by: 56
References: 113
Citations by year: 2026: 7 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 11 · 2021: 11 · 2020: 1
FWCI: 4.81
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Molecular Neurodegeneration (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, cc-by-nc-nd)
RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
Repositorio Institucional de la Universidad de Huelva (Universidad de Huelva) (submittedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Hispana (submittedVersion, cc-by-nc-nd)
idUS (Universidad de Sevilla) (submittedVersion, cc-by-nc-nd)
Repositorio Institucional de la Universidad de Huelva (Universidad de Huelva) (submittedVersion, cc-by-nc-nd)
RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, other-oa)
Funders: Agència de Gestió d’Ajuts Universitaris i de Recerca (2017 SGR1780, 2017 SGR547)
Ministerio de Economía, Industria y Competitividad, Gobierno de España (BES-2017-080303, BFU2016-75107-P)
Fundació la Marató de TV3 (TV3-20141430, TV3-20141432, TV3-20141431)
Ministerio de Ciencia e Innovación (BFU2015-68149-R)
Instituto de Salud Carlos III (PI18/01557)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: APOE ε4, astrocytes, calcium signaling, lysosomal dysfunction, sex differences, Alzheimer's disease, cholesterol distribution, extracellular lipids, calcium flux, hippocampus, intracellular calcium stores
MeSH terms: Alzheimer Disease, Animals, Astrocytes, Calcium, Cholesterol, Female, Hippocampus, Lysosomes, Male, Mice, Transgenic, Neurons, Apolipoprotein E3, Apolipoprotein E4

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Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice

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