The Impact of the APOEε4 on the Number of Neurons and Gene Expression of Degenerating Neurons in the Dorsolateral Prefrontal Cortex in Alzheimer’s Patients
Alzheimer’s disease (AD) is highly prevalent in the elderly population and leads to AD patients’ higher mortality, low life quality, and lead to a huge economic burden on the health system. Even though the APOEε4 gene has been identified as a risk factor for the late onset of AD, there are no studies to examine the impact of APOEε4 on the neural and gene expression mechanisms of cognitive impairment in AD. Our study examined the impact of APOEε4 on AD patients’ cognitive function and the level of a hallmark of AD pathology. This study also examined the impact of APOEε4 on the number of neurons in the dorsolateral prefrontal cortex (DLPFC)and the gene expression of degenerating neurons. This study used data from one publicly available dataset called the Seattle Alzheimer’s Disease Brain Cell Atlas consortium (SEA-AD), including 75 AD patients (M = 88.56 years, SD = 7.89). T-tests revealed a significant difference in participants’ age at death, cognitive status, age of onset cognitive symptoms, cognitive abilities screening instrument score, mini-mental state examination score, montreal cognitive assessment score, and the percentage of Sst chodl, L6 b, and L5/6 NP cells between APOEε4 carriers and non-carriers. Single-cell RNA sequence revealed that APOEε4 led to a significantly less gene expression of the GLRA1 gene in Sst chodl neurons and KCNA1 gene in L5/6 NP neurons. The present findings provide insight for enhancing understanding of the cause of AD and AD’s cognitive impairment from an APOEε4 perspective.
References
[1]
Alzheimer’s Association (2016) Alzheimer’s Disease Facts and Figures. Alzheimer’s & Dementia, 12, 459-509. https://doi.org/10.1016/j.jalz.2016.03.001
[2]
Alzheimer’s Association (2024) Alzheimer’s Disease Facts and Figures. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 20, 3708-3821.
[3]
World Health Organization and Alzheimer’s Disease International (2012) Dementia: A Public Health Priority.
[4]
Cass, S.P. (2017) Alzheimer’s Disease and Exercise: A Literature Review. Current Sports Medicine Reports, 16, 19-22. https://doi.org/10.1249/jsr.0000000000000332
[5]
Glenthøj, L.B., Jepsen, J.R.M., Hjorthøj, C., Bak, N., Kristensen, T.D., Wenneberg, C., et al. (2016) Negative Symptoms Mediate the Relationship between Neurocognition and Function in Individuals at Ultrahigh Risk for Psychosis. Acta Psychiatrica Scandinavica, 135, 250-258. https://doi.org/10.1111/acps.12682
[6]
Barnes, J.N. (2015) Exercise, Cognitive Function, and Aging. Advances in Physiology Education, 39, 55-62. https://doi.org/10.1152/advan.00101.2014
[7]
Guo, T., Zhang, D., Zeng, Y., Huang, T.Y., Xu, H. and Zhao, Y. (2020) Molecular and Cellular Mechanisms Underlying the Pathogenesis of Alzheimer’s Disease. Molecular Neurodegeneration, 15, Article No. 40. https://doi.org/10.1186/s13024-020-00391-7
[8]
de Ture, M.A. and Dickson, D.W. (2019) The Neuropathological Diagnosis of Alzheimer’s Disease. Molecular Neurodegeneration, 14, Article No. 32. https://doi.org/10.1186/s13024-019-0333-5
[9]
Serrano-Pozo, A., Frosch, M.P., Masliah, E. and Hyman, B.T. (2011) Neuropathological Alterations in Alzheimer Disease. Cold Spring Harbor Perspectives in Medicine, 1, a006189. https://doi.org/10.1101/cshperspect.a006189
[10]
Barber, R.C. (2012) The Genetics of Alzheimer’s Disease. Scientifica, 2012, 1-14. https://doi.org/10.6064/2012/246210
[11]
Wightman, D.P., Jansen, I.E., Savage, J.E., Shadrin, A.A., Bahrami, S., Holland, D., etal. (2021) A Genome-Wide Association Study with 1,126,563 Individuals Identifies New Risk Loci for Alzheimer’s Disease. Nature Genetics, 53, 1276-1282. https://doi.org/10.1038/s41588-021-00921-z
[12]
Liu, C., Kanekiyo, T., Xu, H. and Bu, G. (2013) Apolipoprotein E and Alzheimer Disease: Risk, Mechanisms and Therapy. Nature Reviews Neurology, 9, 106-118. https://doi.org/10.1038/nrneurol.2012.263
[13]
Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S., et al. (1993) Apolipoprotein E: High-Avidity Binding to Beta-Amyloid and Increased Frequency of Type 4 Allele in Late-Onset Familial Alzheimer Disease. Proceedings of the National Academy of Sciences, 90, 1977-1981. https://doi.org/10.1073/pnas.90.5.1977
[14]
Gharbi-Meliani, A., Dugravot, A., Sabia, S., Regy, M., Fayosse, A., Schnitzler, A., etal. (2021) The Association of APOE Ε4 with Cognitive Function over the Adult Life Course and Incidence of Dementia: 20 Years Follow-Up of the Whitehall II Study. Alzheimer’s Research & Therapy, 13, Article No. 5. https://doi.org/10.1186/s13195-020-00740-0
[15]
Olichney, J.M., Sabbagh, M.N., Hofstetter, C.R., Galasko, D., Grundman, M., Katzman, R., et al. (1997) The Impact of Apolipoprotein E4 on Cause of Death in Alzheimer’s Disease. Neurology, 49, 76-81. https://doi.org/10.1212/wnl.49.1.76
[16]
Sando, S.B., Melquist, S., Cannon, A., Hutton, M.L., Sletvold, O., Saltvedt, I., et al. (2008) APOE Ε4 Lowers Age at Onset and Is a High Risk Factor for Alzheimer’s Disease; a Case Control Study from Central Norway. BMC Neurology, 8, Article No. 9. https://doi.org/10.1186/1471-2377-8-9
[17]
Fleisher, A.S., Chen, K., Liu, X., Ayutyanont, N., Roontiva, A., Thiyyagura, P., et al. (2013) Apolipoprotein E Ε4 and Age Effects on Florbetapir Positron Emission Tomography in Healthy Aging and Alzheimer Disease. Neurobiology of Aging, 34, 1-12. https://doi.org/10.1016/j.neurobiolaging.2012.04.017
[18]
Gonneaud, J., Arenaza-Urquijo, E.M., Fouquet, M., Perrotin, A., Fradin, S., de La Sayette, V., et al. (2016) Relative Effect of APOE Ε4 on Neuroimaging Biomarker Changes across the Lifespan. Neurology, 87, 1696-1703. https://doi.org/10.1212/wnl.0000000000003234
[19]
Kantarci, K., Lowe, V., Przybelski, S.A., Weigand, S.D., Senjem, M.L., Ivnik, R.J., etal. (2012) APOE Modifies the Association between Aβ Load and Cognition in Cognitively Normal Older Adults. Neurology, 78, 232-240. https://doi.org/10.1212/wnl.0b013e31824365ab
[20]
Kok, E., Haikonen, S., Luoto, T., Huhtala, H., Goebeler, S., Haapasalo, H., et al. (2009) Apolipoprotein E-Dependent Accumulation of Alzheimer Disease-Related Lesions Begins in Middle Age. Annals of Neurology, 65, 650-657. https://doi.org/10.1002/ana.21696
[21]
Polvikoski, T., Sulkava, R., Haltia, M., Kainulainen, K., Vuorio, A., Verkkoniemi, A., et al. (1995) Apolipoprotein E, Dementia, and Cortical Deposition of Β-Amyloid Protein. New England Journal of Medicine, 333, 1242-1248. https://doi.org/10.1056/nejm199511093331902
[22]
Verghese, P.B., Castellano, J.M., Garai, K., Wang, Y., Jiang, H., Shah, A., et al. (2013) APOE Influences Amyloid-Β (aβ) Clearance Despite Minimal APOE/aβ Association in Physiological Conditions. Proceedings of the National Academy of Sciences, 110, E1809-E1816. https://doi.org/10.1073/pnas.1220484110
[23]
Wildsmith, K.R., Holley, M., Savage, J.C., Skerrett, R. and Landreth, G.E. (2013) Evidence for Impaired Amyloid Β Clearance in Alzheimer’s Disease. Alzheimer’s Research & Therapy, 5, Article No. 33. https://doi.org/10.1186/alzrt187
[24]
Koffie, R.M., Hashimoto, T., Tai, H., Kay, K.R., Serrano-Pozo, A., Joyner, D., et al. (2012) Apolipoprotein E4 Effects in Alzheimer’s Disease Are Mediated by Synaptotoxic Oligomeric Amyloid-β. Brain, 135, 2155-2168. https://doi.org/10.1093/brain/aws127
[25]
Stevens, D.A., Workman, C.I., Kuwabara, H., Butters, M.A., Savonenko, A., Nassery, N., et al. (2022) Regional Amyloid Correlates of Cognitive Performance in Ageing and Mild Cognitive Impairment. Brain Communications, 4, fcac016. https://doi.org/10.1093/braincomms/fcac016
[26]
Zhang, H., Jiang, X., Ma, L., Wei, W., Li, Z., Chang, S., et al. (2022) Role of Aβ in Alzheimer’s-Related Synaptic Dysfunction. Frontiers in Cell and Developmental Biology, 10, Article 964075. https://doi.org/10.3389/fcell.2022.964075
[27]
Therriault, J., Benedet, A.L., Pascoal, T.A., Mathotaarachchi, S., Chamoun, M., Savard, M., et al. (2020) Association of Apolipoprotein E Ε4 with Medial Temporal Tau Independent of Amyloid-β. JAMA Neurology, 77, 470-479. https://doi.org/10.1001/jamaneurol.2019.4421
[28]
Rawat, P., Sehar, U., Bisht, J., Selman, A., Culberson, J. and Reddy, P.H. (2022) Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies. International Journal of Molecular Sciences, 23, Article 12841. https://doi.org/10.3390/ijms232112841
[29]
Wang, C., Xiong, M., Gratuze, M., Bao, X., Shi, Y., Andhey, P.S., et al. (2021) Selective Removal of Astrocytic APOE4 Strongly Protects against Tau-Mediated Neurodegeneration and Decreases Synaptic Phagocytosis by Microglia. Neuron, 109, 1657-1674.e7. https://doi.org/10.1016/j.neuron.2021.03.024
[30]
Fernández-Pérez, E.J., Gallegos, S., Armijo-Weingart, L., Araya, A., Riffo-Lepe, N.O., Cayuman, F., et al. (2020) Changes in Neuronal Excitability and Synaptic Transmission in Nucleus Accumbens in a Transgenic Alzheimer’s Disease Mouse Model. Scientific Reports, 10, Article No. 19606. https://doi.org/10.1038/s41598-020-76456-w
[31]
Foust, A.J., Yu, Y., Popovic, M., Zecevic, D. and McCormick, D.A. (2011) Somatic Membrane Potential and Kv1 Channels Control Spike Repolarization in Cortical Axon Collaterals and Presynaptic Boutons. The Journal of Neuroscience, 31, 15490-15498. https://doi.org/10.1523/jneurosci.2752-11.2011
[32]
Jan, L.Y. and Jan, Y.N. (2012) Voltage-Gated Potassium Channels and the Diversity of Electrical Signalling. The Journal of Physiology, 590, 2591-2599. https://doi.org/10.1113/jphysiol.2011.224212
[33]
Paulhus, K. and Glasscock, E. (2023) Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy. International Journal of Molecular Sciences, 24, Article 8826. https://doi.org/10.3390/ijms24108826
[34]
Li, S. and Selkoe, D.J. (2020) A Mechanistic Hypothesis for the Impairment of Synaptic Plasticity by Soluble Aβ Oligomers from Alzheimer’s Brain. Journal of Neurochemistry, 154, 583-597. https://doi.org/10.1111/jnc.15007
[35]
Talantova, M., Sanz-Blasco, S., Zhang, X., Xia, P., Akhtar, M.W., Okamoto, S., et al. (2013) Aβ Induces Astrocytic Glutamate Release, Extrasynaptic NMDA Receptor Activation, and Synaptic Loss. Proceedings of the National Academy of Sciences, 110, E2518-E2527. https://doi.org/10.1073/pnas.1306832110
[36]
Wang, R. and Reddy, P.H. (2017) Role of Glutamate and NMDA Receptors in Alzheimer’s Disease. Journal of Alzheimer’s Disease, 57, 1041-1048. https://doi.org/10.3233/jad-160763
[37]
Consens, M.E., Chen, Y., Menon, V., Wang, Y., Schneider, J.A., De Jager, P.L., et al. (2022) Bulk and Single-Nucleus Transcriptomics Highlight Intra-Telencephalic and Somatostatin Neurons in Alzheimer’s Disease. Frontiers in Molecular Neuroscience, 15, Article 903175. https://doi.org/10.3389/fnmol.2022.903175
[38]
Joshi, A., Giorgi, F.M. and Sanna, P.P. (2024) Transcriptional Patterns in Stages of Alzheimer’s Disease Are Cell-Type-Specific and Partially Converge with the Effects of Alcohol Use Disorder in Humans. eNeuro, 11, ENEURO.0118-24.2024. https://doi.org/10.1523/eneuro.0118-24.2024
Kumar, S., Zomorrodi, R., Ghazala, Z., Goodman, M.S., Blumberger, D.M., Cheam, A., et al. (2017) Extent of Dorsolateral Prefrontal Cortex Plasticity and Its Association with Working Memory in Patients with Alzheimer Disease. JAMA Psychiatry, 74, 1266-1274. https://doi.org/10.1001/jamapsychiatry.2017.3292
[41]
Bakken, T.E., Jorstad, N.L., Hu, Q., Lake, B.B., Tian, W., Kalmbach, B.E., et al. (2021) Comparative Cellular Analysis of Motor Cortex in Human, Marmoset and Mouse. Nature, 598, 111-119. https://doi.org/10.1038/s41586-021-03465-8
Miller, J.A., Gouwens, N.W., Tasic, B., Collman, F., et al. (2020) Common Cell Type Nomenclature for the Mammalian Brain. ELife, 9, e59928.
[44]
Patiño, M., Lagos, W.N., Patne, N.S., Tasic, B., Zeng, H. and Callaway, E.M. (2022) Single-Cell Transcriptomic Classification of Rabies-Infected Cortical Neurons. Proceedings of the National Academy of Sciences, 119, e2203677119. https://doi.org/10.1073/pnas.2203677119
[45]
Zhang, M., Eichhorn, S.W., Zingg, B., Yao, Z., Cotter, K., Zeng, H., et al. (2021) Spatially Resolved Cell Atlas of the Mouse Primary Motor Cortex by Merfish. Nature, 598, 137-143. https://doi.org/10.1038/s41586-021-03705-x
[46]
Colom-Cadena, M., Spires-Jones, T., Zetterberg, H., Blennow, K., Caggiano, A., DeKosky, S.T., et al. (2020) The Clinical Promise of Biomarkers of Synapse Damage or Loss in Alzheimer’s Disease. Alzheimer’s Research & Therapy, 12, Article No. 21. https://doi.org/10.1186/s13195-020-00588-4
[47]
Lauterborn, J.C., Scaduto, P., Cox, C.D., Schulmann, A., Lynch, G., Gall, C.M., et al. (2021) Increased Excitatory to Inhibitory Synaptic Ratio in Parietal Cortex Samples from Individuals with Alzheimer’s Disease. Nature Communications, 12, Article No. 2603. https://doi.org/10.1038/s41467-021-22742-8
[48]
Scaduto, P., Lauterborn, J.C., Cox, C.D., Fracassi, A., Zeppillo, T., Gutierrez, B.A., et al. (2022) Functional Excitatory to Inhibitory Synaptic Imbalance and Loss of Cognitive Performance in People with Alzheimer’s Disease Neuropathologic Change. Acta Neuropathologica, 145, 303-324. https://doi.org/10.1007/s00401-022-02526-0
[49]
Dutertre, S., Becker, C. and Betz, H. (2012) Inhibitory Glycine Receptors: An Update. Journal of Biological Chemistry, 287, 40216-40223. https://doi.org/10.1074/jbc.r112.408229
[50]
Lynch, J.W. (2004) Molecular Structure and Function of the Glycine Receptor Chloride Channel. Physiological Reviews, 84, 1051-1095. https://doi.org/10.1152/physrev.00042.2003
[51]
Armijo-Weingart, L., San Martin, L., Gallegos, S., Araya, A., Konar-Nie, M., Fernandez-Pérez, E., et al. (2024) Loss of Glycine Receptors in the Nucleus Accumbens and Ethanol Reward in an Alzheimer’s Disease Mouse Model. Progress in Neurobiology, 237, Article 102616. https://doi.org/10.1016/j.pneurobio.2024.102616
[52]
Goldberg, E.M., Clark, B.D., Zagha, E., Nahmani, M., Erisir, A. and Rudy, B. (2008) K+ Channels at the Axon Initial Segment Dampen Near-Threshold Excitability of Neocortical Fast-Spiking Gabaergic Interneurons. Neuron, 58, 387-400. https://doi.org/10.1016/j.neuron.2008.03.003
[53]
Kole, M.H.P., Letzkus, J.J. and Stuart, G.J. (2007) Axon Initial Segment Kv1 Channels Control Axonal Action Potential Waveform and Synaptic Efficacy. Neuron, 55, 633-647. https://doi.org/10.1016/j.neuron.2007.07.031
[54]
Pathak, D., Guan, D. and Foehring, R.C. (2016) Roles of Specific Kv Channel Types in Repolarization of the Action Potential in Genetically Identified Subclasses of Pyramidal Neurons in Mouse Neocortex. Journal of Neurophysiology, 115, 2317-2329. https://doi.org/10.1152/jn.01028.2015
[55]
Lanznaster, D., Mack, J.M., Coelho, V., Ganzella, M., Almeida, R.F., Dal-Cim, T., etal. (2016) Guanosine Prevents Anhedonic-Like Behavior and Impairment in Hippocampal Glutamate Transport Following Amyloid-β1-40 Administration in Mice. Molecular Neurobiology, 54, 5482-5496. https://doi.org/10.1007/s12035-016-0082-1
[56]
Scimemi, A., Meabon, J.S., Woltjer, R.L., Sullivan, J.M., Diamond, J.S. and Cook, D.G. (2013) Amyloid-β1–42Slows Clearance of Synaptically Released Glutamate by Mislocalizing Astrocytic GLT-1. The Journal of Neuroscience, 33, 5312-5318. https://doi.org/10.1523/jneurosci.5274-12.2013
[57]
Ribarič, S. (2023) Detecting Early Cognitive Decline in Alzheimer’s Disease with Brain Synaptic Structural and Functional Evaluation. Biomedicines, 11, Article 355. https://doi.org/10.3390/biomedicines11020355
[58]
Dauth, S., Maoz, B.M., Sheehy, S.P., Hemphill, M.A., Murty, T., Macedonia, M.K., etal. (2017) Neurons Derived from Different Brain Regions Are Inherently Different in Vitro: A Novel Multiregional Brain-on-a-Chip. Journal of Neurophysiology, 117, 1320-1341. https://doi.org/10.1152/jn.00575.2016
[59]
Jacobs, H.I.L., Van Boxtel, M.P.J., Jolles, J., Verhey, F.R.J. and Uylings, H.B.M. (2012) Parietal Cortex Matters in Alzheimer’s Disease: An Overview of Structural, Functional and Metabolic Findings. Neuroscience & Biobehavioral Reviews, 36, 297-309. https://doi.org/10.1016/j.neubiorev.2011.06.009
[60]
Migliaccio, R. and Cacciamani, F. (2022) The Temporal Lobe in Typical and Atypical Alzheimer Disease. In: Handbook of Clinical Neurology, Elsevier, 449-466. https://doi.org/10.1016/b978-0-12-823493-8.00004-3
