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Illuminating Neural Circuits in Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and there is currently no cure. Neural circuit dysfunction is the fundamental mechanism underlying the learning and memory deficits in patients with AD. Therefore, it is important to understand the structural features and mechanisms underlying the deregulated circuits during AD progression, by which new tools for intervention can be developed. Here, we briefly summarize the most recently established cutting-edge experimental approaches and key techniques that enable neural circuit tracing and manipulation of their activity. We also discuss the advantages and limitations of these approaches. Finally, we review the applications of these techniques in the discovery of circuit mechanisms underlying β-amyloid and tau pathologies during AD progression, and as well as the strategies for targeted AD treatments.

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References

  1. Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer’s disease: Occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci 2009, 11: 111–128.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kumar A, Singh A, Ekavali. A review on Alzheimer's disease pathophysiology and its management: An update. Pharmacol Rep 2015, 67: 195–203.

  3. Gu XM, Jiang ZF, Huang HC. Magnetic resonance imaging of Alzheimer’s disease: From diagnosis to therapeutic evaluation. Chin J Integr Med 2010, 16: 276–282.

    Article  CAS  PubMed  Google Scholar 

  4. Harrison TM, Maass A, Adams JN, Du R, Baker SL, Jagust WJ. Tau deposition is associated with functional isolation of the Hippocampus in aging. Nat Commun 2019, 10: 4900.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell 2016, 164: 603–615.

    Article  PubMed  CAS  Google Scholar 

  6. Svensson V, Vento-Tormo R, Teichmann SA. Exponential scaling of single-cell RNA-seq in the past decade. Nat Protoc 2018, 13: 599–604.

    Article  CAS  PubMed  Google Scholar 

  7. Rossier J, Bernard A, Cabungcal JH, Perrenoud Q, Savoye A, Gallopin T. Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin. Mol Psychiatry 2015, 20: 154–161.

    Article  CAS  PubMed  Google Scholar 

  8. Subkhankulova T, Yano K, Robinson HP, Livesey FJ. Grouping and classifying electrophysiologically-defined classes of neocortical neurons by single cell, whole-genome expression profiling. Front Mol Neurosci 2010, 3: 10.

    PubMed  PubMed Central  Google Scholar 

  9. Hashimshony T, Senderovich N, Avital G, Klochendler A, de Leeuw Y, Anavy L, et al. CEL-Seq2: Sensitive highly-multiplexed single-cell RNA-Seq. Genome Biol 2016, 17: 77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, La Manno G, Juréus A, et al. Brain structure Cell types in the mouse cortex and Hippocampus revealed by single-cell RNA-seq. Science 2015, 347: 1138–1142.

    Article  CAS  PubMed  Google Scholar 

  11. Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou DH, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci 2015, 18: 145–153.

    Article  CAS  PubMed  Google Scholar 

  12. Wu AR, Neff NF, Kalisky T, Dalerba P, Treutlein B, Rothenberg ME, et al. Quantitative assessment of single-cell RNA-sequencing methods. Nat Methods 2014, 11: 41–46.

    Article  CAS  PubMed  Google Scholar 

  13. Pollen AA, Nowakowski TJ, Shuga J, Wang XH, Leyrat AA, Lui JH, et al. Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex. Nat Biotechnol 2014, 32: 1053–1058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Prakadan SM, Shalek AK, Weitz DA. Scaling by shrinking: Empowering single-cell ‘omics’ with microfluidic devices. Nat Rev Genet 2017, 18: 345–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 2015, 161: 1202–1214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Klein AM, Mazutis L, Akartuna I, Tallapragada N, Veres A, Li V, et al. Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell 2015, 161: 1187–1201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang XN, Li TQ, Liu F, Chen YQ, Yao JC, Li ZY, et al. Comparative analysis of droplet-based ultra-high-throughput single-cell RNA-seq systems. Mol Cell 2019, 73: 130-142.e5.

    Article  PubMed  Google Scholar 

  18. Zheng GX, Terry JM, Belgrader P, Ryvkin P, Bent ZW, Wilson R, et al. Massively parallel digital transcriptional profiling of single cells. Nat Commun 2017, 8: 14049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mathys H, Davila-Velderrain J, Peng ZY, Gao F, Mohammadi S, Young JZ, et al. Author Correction: Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 2019, 571: E1. https://doi.org/10.1038/s41586-019-1329-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lake BB, Ai R, Kaeser GE, Salathia NS, Yung YC, Liu R, et al. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Science 2016, 352: 1586–1590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Krishnaswami SR, Grindberg RV, Novotny M, Venepally P, Lacar B, Bhutani K, et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat Protoc 2016, 11: 499–524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lake BB, Chen S, Sos BC, Fan J, Kaeser GE, Yung YC, et al. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat Biotechnol 2018, 36: 70–80.

    Article  CAS  PubMed  Google Scholar 

  23. Lake BB, Codeluppi S, Yung YC, Gao D, Chun J, Kharchenko PV, et al. A comparative strategy for single-nucleus and single-cell transcriptomes confirms accuracy in predicted cell-type expression from nuclear RNA. Sci Rep 2017, 7: 6031.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Ziegenhain C, Vieth B, Parekh S, Reinius B, Guillaumet-Adkins A, Smets M, et al. Comparative analysis of single-cell RNA sequencing methods. Mol Cell 2017, 65: 631-643.e4.

    Article  CAS  PubMed  Google Scholar 

  25. Phipson B, Zappia L, Oshlack A. Gene length and detection bias in single cell RNA sequencing protocols. F1000Res 2017, 6: 595.

  26. Wu AR, Wang JB, Streets AM, Huang YY. Single-cell transcriptional analysis. Annu Rev Anal Chem (Palo Alto Calif) 2017, 10: 439–462.

    Article  CAS  Google Scholar 

  27. Saliba AE, Westermann AJ, Gorski SA, Vogel J. Single-cell RNA-seq: Advances and future challenges. Nucleic Acids Res 2014, 42: 8845–8860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Crosetto N, Bienko M, van Oudenaarden A. Spatially resolved transcriptomics and beyond. Nat Rev Genet 2015, 16: 57–66.

    Article  CAS  PubMed  Google Scholar 

  29. Zeng HK, Sanes JR. Neuronal cell-type classification: Challenges, opportunities and the path forward. Nat Rev Neurosci 2017, 18: 530–546.

    Article  CAS  PubMed  Google Scholar 

  30. Lein E, Borm LE, Linnarsson S. The promise of spatial transcriptomics for neuroscience in the era of molecular cell typing. Science 2017, 358: 64–69.

    Article  CAS  PubMed  Google Scholar 

  31. Raj A, van den Bogaard P, Rifkin SA, van Oudenaarden A, Tyagi S. Imaging individual mRNA molecules using multiple singly labeled probes. Nat Methods 2008, 5: 877–879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shah S, Lubeck E, Zhou W, Cai L. In situ transcription profiling of single cells reveals spatial organization of cells in the mouse Hippocampus. Neuron 2016, 92: 342–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lubeck E, Coskun AF, Zhiyentayev T, Ahmad M, Cai L. Single-cell in situ RNA profiling by sequential hybridization. Nat Methods 2014, 11: 360–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pi GL, Gao D, Wu DQ, Wang YL, Lei HY, Zeng WB, et al. Posterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect. Nat Commun 2020, 11: 183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dum RP, Levinthal DJ, Strick PL. The spinothalamic system targets motor and sensory areas in the cerebral cortex of monkeys. J Neurosci 2009, 29: 14223–14235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McGovern AE, Davis-Poynter N, Farrell MJ, Mazzone SB. Transneuronal tracing of airways-related sensory circuitry using Herpes simplex virus 1, strain H129. Neuroscience 2012, 207: 148–166.

    Article  CAS  PubMed  Google Scholar 

  37. Su P, Wang HD, Xia JJ, Zhong X, Hu L, Li YL, et al. Evaluation of retrograde labeling profiles of HSV1 H129 anterograde tracer. J Chem Neuroanat 2019, 100: 101662.

    Article  CAS  PubMed  Google Scholar 

  38. Wojaczynski GJ, Engel EA, Steren KE, Enquist LW, Patrick Card J. The neuroinvasive profiles of H129 (Herpes simplex virus type 1) recombinants with putative anterograde-only transneuronal spread properties. Brain Struct Funct 2015, 220: 1395–1420.

    Article  CAS  PubMed  Google Scholar 

  39. Kit S, Kit M, Pirtle EC. Attenuated properties of thymidine kinase-negative deletion mutant of pseudorabies virus. Am J Vet Res 1985, 46: 1359–1367.

    CAS  PubMed  Google Scholar 

  40. Roberts A, Buonocore L, Price R, Forman J, Rose JK. Attenuated vesicular stomatitis viruses as vaccine vectors. J Virol 1999, 73: 3723–3732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lichty BD, Power AT, Stojdl DF, Bell JC. Vesicular stomatitis virus: Re-inventing the bullet. Trends Mol Med 2004, 10: 210–216.

    Article  CAS  PubMed  Google Scholar 

  42. Hastie E, Cataldi M, Marriott I, Grdzelishvili VZ. Understanding and altering cell tropism of vesicular stomatitis virus. Virus Res 2013, 176: 16–32.

    Article  CAS  PubMed  Google Scholar 

  43. van den Pol AN, Ozduman K, Wollmann G, Ho WS, Simon I, Yao Y, et al. Viral strategies for studying the brain, including a replication-restricted self-amplifying delta-G vesicular stomatis virus that rapidly expresses transgenes in brain and can generate a multicolor Golgi-like expression. J Comp Neurol 2009, 516: 456–481.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Beier KT, Saunders A, Oldenburg IA, Miyamichi K, Akhtar N, Luo L, et al. Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular stomatitis virus vectors. PNAS 2011, 108: 15414–15419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zingg B, Chou XL, Zhang ZG, Mesik L, Liang FX, Tao HW, et al. AAV-mediated anterograde transsynaptic tagging: Mapping corticocollicular input-defined neural pathways for defense behaviors. Neuron 2017, 93: 33–47.

    Article  CAS  PubMed  Google Scholar 

  46. Hollis Ii ER, Kadoya K, Hirsch M, Samulski RJ, Tuszynski MH. Efficient retrograde neuronal transduction utilizing self-complementary AAV1. Mol Ther 2008, 16: 296–301.

    Article  PubMed  CAS  Google Scholar 

  47. Wickersham IR, Lyon DC, Barnard RJ, Mori T, Finke S, Conzelmann KK, et al. Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 2007, 53: 639–647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wall NR, Wickersham IR, Cetin A, De La Parra M, Callaway EM. Monosynaptic circuit tracing in vivo through Cre-dependent targeting and complementation of modified rabies virus. Proc Natl Acad Sci USA 2010, 107: 21848–21853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wickersham IR, Finke S, Conzelmann KK, Callaway EM. Retrograde neuronal tracing with a deletion-mutant rabies virus. Nat Methods 2007, 4: 47–49.

    Article  CAS  PubMed  Google Scholar 

  50. Schwarz LA, Miyamichi K, Gao XJ, Beier KT, Weissbourd B, DeLoach KE, et al. Viral-genetic tracing of the input-output organization of a central noradrenaline circuit. Nature 2015, 524: 88–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chatterjee S, Sullivan HA, MacLennan BJ, Xu R, Hou YY, Lavin TK, et al. Nontoxic, double-deletion-mutant rabies viral vectors for retrograde targeting of projection neurons. Nat Neurosci 2018, 21: 638–646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Albertini AA, Ruigrok RW, Blondel D. Rabies virus transcription and replication. Adv Virus Res 2011, 79: 1–22.

    Article  CAS  PubMed  Google Scholar 

  53. Boyden ES. A history of optogenetics: The development of tools for controlling brain circuits with light. F1000 Biol Rep 2011, 3: 11.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Deisseroth K. Optogenetics. Nat Methods 2011, 8: 26–29.

    Article  CAS  PubMed  Google Scholar 

  55. Matsuno-Yagi A, Mukohata Y. Two possible roles of bacteriorhodopsin; a comparative study of strains of Halobacterium halobium differing in pigmentation. Biochem Biophys Res Commun 1977, 78: 237–243.

    Article  CAS  PubMed  Google Scholar 

  56. Nagel G, Ollig D, Fuhrmann M, Kateriya S, Musti AM, Bamberg E, et al. Channelrhodopsin-1: a light-gated proton channel in green algae. Science 2002, 296: 2395–2398.

    Article  CAS  PubMed  Google Scholar 

  57. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci 2005, 8: 1263–1268.

    Article  CAS  PubMed  Google Scholar 

  58. Aravanis AM, Wang LP, Zhang F, Meltzer LA, Mogri MZ, Schneider MB, et al. An optical neural interface: In vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J Neural Eng 2007, 4: S143–S156.

    Article  PubMed  Google Scholar 

  59. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007, 450: 420–424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kato HE, Zhang F, Yizhar O, Ramakrishnan C, Nishizawa T, Hirata K, et al. Crystal structure of the channelrhodopsin light-gated cation channel. Nature 2012, 482: 369–374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Deisseroth K. Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci 2015, 18: 1213–1225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schneider F, Grimm C, Hegemann P. Biophysics of channelrhodopsin. Annu Rev Biophys 2015, 44: 167–186.

    Article  CAS  PubMed  Google Scholar 

  63. Nagel G, Brauner M, Liewald JF, Adeishvili N, Bamberg E, Gottschalk A. Light activation of channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses. Curr Biol 2005, 15: 2279–2284.

    Article  CAS  PubMed  Google Scholar 

  64. Lin JY, Lin MZ, Steinbach P, Tsien RY. Characterization of engineered channelrhodopsin variants with improved properties and kinetics. Biophys J 2009, 96: 1803–1814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gunaydin LA, Yizhar O, Berndt A, Sohal VS, Deisseroth K, Hegemann P. Ultrafast optogenetic control. Nat Neurosci 2010, 13: 387–392.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang F, Prigge M, Beyrière F, Tsunoda SP, Mattis J, Yizhar O, et al. Red-shifted optogenetic excitation: A tool for fast neural control derived from Volvox carteri. Nat Neurosci 2008, 11: 631–633.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Lin JY, Knutsen PM, Muller A, Kleinfeld D, Tsien RY. ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation. Nat Neurosci 2013, 16: 1499–1508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hochbaum DR, Zhao YX, Farhi SL, Klapoetke N, Werley CA, Kapoor V, et al. All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins. Nat Methods 2014, 11: 825–833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chow BY, Han X, Dobry AS, Qian XF, Chuong AS, Li MJ, et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps. Nature 2010, 463: 98–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wietek J, Wiegert JS, Adeishvili N, Schneider F, Watanabe H, Tsunoda SP, et al. Conversion of channelrhodopsin into a light-gated chloride channel. Science 2014, 344: 409–412.

    Article  CAS  PubMed  Google Scholar 

  71. Atasoy D, Sternson SM. Chemogenetic tools for causal cellular and neuronal biology. Physiol Rev 2018, 98: 391–418.

    Article  CAS  PubMed  Google Scholar 

  72. Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S, Forsayeth JR, et al. Engineering GPCR signaling pathways with RASSLs. Nat Methods 2008, 5: 673–678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Alexander GM, Rogan SC, Abbas AI, Armbruster BN, Pei Y, Allen JA, et al. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 2009, 63: 27–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Stachniak TJ, Ghosh A, Sternson SM. Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus→midbrain pathway for feeding behavior. Neuron 2014, 82: 797–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gomez JL, Bonaventura J, Lesniak W, Mathews WB, Sysa-Shah P, Rodriguez LA, et al. Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science 2017, 357: 503–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Todd WD, Fenselau H, Wang JL, Zhang R, Machado NL, Venner A, et al. A hypothalamic circuit for the circadian control of aggression. Nat Neurosci 2018, 21: 717–724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rodriguez GA, Barrett GM, Duff KE, Hussaini SA. Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces Aβ and tau pathology in the Hippocampus. PLoS Biol 2020, 18: e3000851. https://doi.org/10.1371/journal.pbio.3000851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991, 82: 239–259.

    Article  CAS  PubMed  Google Scholar 

  79. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 2011, 1: a006189.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Devanand DP, Pradhaban G, Liu X, Khandji A, De Santi S, Segal S, et al. Hippocampal and entorhinal atrophy in mild cognitive impairment: Prediction of Alzheimer disease. Neurology 2007, 68: 828–836.

    Article  CAS  PubMed  Google Scholar 

  81. Busche MA, Hyman BT. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat Neurosci 2020, 23: 1183–1193.

    Article  CAS  PubMed  Google Scholar 

  82. Zhou YY, Song WM, Andhey PS, Swain A, Levy T, Miller KR, et al. Author Correction: Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med 2020, 26: 981.

    Article  CAS  PubMed  Google Scholar 

  83. Huijbers W, Mormino EC, Schultz AP, Wigman S, Ward AM, Larvie M, et al. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. Brain 2015, 138: 1023–1035.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 2008, 321: 1686–1689.

    Article  CAS  PubMed  Google Scholar 

  85. Zott B, Simon MM, Hong W, Unger F, Chen-Engerer HJ, Frosch MP, et al. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science 2019, 365: 559–565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Matos M, Augusto E, Machado NJ, dos Santos-Rodrigues A, Cunha RA, Agostinho P. Astrocytic adenosine A2A receptors control the amyloid-β peptide-induced decrease of glutamate uptake. J Alzheimers Dis 2012, 31: 555–567.

    Article  CAS  PubMed  Google Scholar 

  87. Canas PM, Porciúncula LO, Cunha GM, Silva CG, Machado NJ, Oliveira JM, et al. Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci 2009, 29: 14741–14751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang DY, Govindaiah G, Liu RJ, De Arcangelis V, Cox CL, Xiang YK. Binding of amyloid beta peptide to beta2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity. FASEB J 2010, 24: 3511–3521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Huang Y, Shen W, Su J, Cheng B, Li D, Liu G, et al. Modulating the balance of synaptic and extrasynaptic NMDA receptors shows positive effects against amyloid-β-induced neurotoxicity. J Alzheimers Dis 2017, 57: 885–897.

    Article  CAS  PubMed  Google Scholar 

  90. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002, 5: 405–414.

    Article  CAS  PubMed  Google Scholar 

  91. Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E, Slutsky I. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci 2009, 12: 1567–1576.

    Article  CAS  PubMed  Google Scholar 

  92. He Y, Wei MD, Wu Y, Qin HP, Li WN, Ma XL, et al. Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4, 5-bisphosphate. Nat Commun 2019, 10: 1193.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Talantova M, Sanz-Blasco S, Zhang XF, Xia P, Akhtar MW, Okamoto S, et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci USA 2013, 110: E2518–E2527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Shankar GM, Li SM, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 2008, 14: 837–842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Leshchyns’ka I, Liew HT, Shepherd C, Halliday GM, Stevens CH, Ke YD, et al. Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease. Nat Commun 2015, 6: 8836.

    Article  CAS  PubMed  Google Scholar 

  96. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 2006, 52: 831–843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hrynchak MV, Rierola M, Golovyashkina N, Penazzi L, Pump WC, David B, et al. Chronic presence of oligomeric aβ differentially modulates spine parameters in the Hippocampus and cortex of mice with low APP transgene expression. Front Synaptic Neurosci 2020, 12: 16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ting JT, Kelley BG, Lambert TJ, Cook DG, Sullivan JM. Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms. Proc Natl Acad Sci USA 2007, 104: 353–358.

    Article  CAS  PubMed  Google Scholar 

  99. Lin L, Liu AY, Li HQ, Feng J, Yan Z. Inhibition of histone methyltransferases EHMT1/2 reverses amyloid-β-induced loss of AMPAR currents in human stem cell-derived cortical neurons. J Alzheimers Dis 2019, 70: 1175–1185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Du YH, Fu M, Huang ZL, Tian X, Li JJ, Pang YY, et al. TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer’s disease. Aging Cell 2020, 19: e13113. https://doi.org/10.1111/acel.13113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Rodrigues EM, Scudder SL, Goo MS, Patrick GN. Aβ-induced synaptic alterations require the E3 ubiquitin ligase Nedd4-1. J Neurosci 2016, 36: 1590–1595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 2005, 8: 1051–1058.

    Article  CAS  PubMed  Google Scholar 

  103. Hsu WL, Ma YL, Hsieh DY, Liu YC, Lee EH. STAT1 negatively regulates spatial memory formation and mediates the memory-impairing effect of Aβ. Neuropsychopharmacology 2014, 39: 746–758.

    Article  CAS  PubMed  Google Scholar 

  104. Yin YL, Gao D, Wang YL, Wang ZH, Wang X, Ye JW, et al. Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling. Proc Natl Acad Sci USA 2016, 113: E3773–E3781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Li XG, Hong XY, Wang YL, Zhang SJ, Zhang JF, Li XC, et al. Tau accumulation triggers STAT1-dependent memory deficits by suppressing NMDA receptor expression. EMBO Rep 2019, 20: e47202.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Ye JW, Yin YL, Liu HH, Fang L, Tao XQ, Wei LY, et al. Tau inhibits PKA by nuclear proteasome-dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation. Aging Cell 2020, 19: e13055. https://doi.org/10.1111/acel.13055.

    Article  CAS  PubMed  Google Scholar 

  107. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 2010, 142: 387–397.

    Article  CAS  PubMed  Google Scholar 

  108. Luo HB, Xia YY, Shu XJ, Liu ZC, Feng Y, Liu XH, et al. SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc Natl Acad Sci USA 2014, 111: 16586–16591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Feng Q, Luo Y, Zhang XN, Yang XF, Hong XY, Sun DS, et al. MAPT/Tau accumulation represses autophagy flux by disrupting IST1-regulated ESCRT-III complex formation: A vicious cycle in Alzheimer neurodegeneration. Autophagy 2020, 16: 641–658.

    Article  CAS  PubMed  Google Scholar 

  110. Wang X, Liu EJ, Liu Q, Li SH, Li T, Zhou QZ, et al. Tau acetylation in entorhinal cortex induces its chronic hippocampal propagation and cognitive deficits in mice. J Alzheimers Dis 2020, 77: 241–255.

    Article  CAS  PubMed  Google Scholar 

  111. Ye JW, Yin Y, Yin YL, Zhang HQ, Wan HL, Wang L, et al. Tau-induced upregulation of C/EBPβ-TRPC1-SOCE signaling aggravates tauopathies: A vicious cycle in Alzheimer neurodegeneration. Aging Cell 2020, 19: e13209. https://doi.org/10.1111/acel.13209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hoover BR, Reed MN, Su JJ, Penrod RD, Kotilinek LA, Grant MK, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010, 68: 1067–1081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tracy TE, Sohn PD, Minami SS, Wang C, Min SW, Li YQ, et al. Acetylated tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 2016, 90: 245–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhao XH, Kotilinek LA, Smith B, Hlynialuk C, Zahs K, Ramsden M, et al. Caspase-2 cleavage of tau reversibly impairs memory. Nat Med 2016, 22: 1268–1276.

    Article  CAS  PubMed  Google Scholar 

  115. Hatch RJ, Wei Y, Xia D, Götz J. Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment. Acta Neuropathol 2017, 133: 717–730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sohn PD, Huang CT, Yan R, Fan L, Tracy TE, Camargo CM, et al. Pathogenic tau impairs axon initial segment plasticity and excitability homeostasis. Neuron 2019, 104: 458-470.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Chen TW, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A, et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 2013, 499: 295–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Jimenez JC, Su K, Goldberg AR, Luna VM, Biane JS, Ordek G, et al. Anxiety cells in a hippocampal-hypothalamic circuit. Neuron 2018, 97: 670-683.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Granholm E, Butters N. Associative encoding and retrieval in Alzheimer’s and Huntington’s disease. Brain Cogn 1988, 7: 335–347.

    Article  CAS  PubMed  Google Scholar 

  120. Roy DS, Arons A, Mitchell TI, Pignatelli M, Ryan TJ, Tonegawa S. Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature 2016, 531: 508–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. He QY, Wang JH, Hu HL. Illuminating the activated brain: Emerging activity-dependent tools to capture and control functional neural circuits. Neurosci Bull 2019, 35: 369–377.

    Article  CAS  PubMed  Google Scholar 

  122. Yang Y, Wang ZH, Jin S, Gao D, Liu N, Chen SP, et al. Opposite monosynaptic scaling of BLP-vCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory. Nat Commun 2016, 7: 11935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci 2016, 19: 1085–1092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Garcia-Marin V, Blazquez-Llorca L, Rodriguez JR, Boluda S, Muntane G, Ferrer I, et al. Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques. Front Neuroanat 2009, 3: 28.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Ramos-Miguel A, Hercher C, Beasley CL, Barr AM, Bayer TA, Falkai P, et al. Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample. Mol Neurodegener 2015, 10: 65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Bell KF, de Kort GJ, Steggerda S, Shigemoto R, Ribeiro-da-Silva A, Cuello AC. Structural involvement of the glutamatergic presynaptic boutons in a transgenic mouse model expressing early onset amyloid pathology. Neurosci Lett 2003, 353: 143–147.

    Article  CAS  PubMed  Google Scholar 

  127. Bell KF, Ducatenzeiler A, Ribeiro-da-Silva A, Duff K, Bennett DA, Cuello AC. The amyloid pathology progresses in a neurotransmitter-specific manner. Neurobiol Aging 2006, 27: 1644–1657.

    Article  CAS  PubMed  Google Scholar 

  128. Sanchez-Mejias E, Nuñez-Diaz C, Sanchez-Varo R, Gomez-Arboledas A, Garcia-Leon JA, Fernandez-Valenzuela JJ, et al. Distinct disease-sensitive GABAergic neurons in the perirhinal cortex of Alzheimer’s mice and patients. Brain Pathol 2020, 30: 345–363.

    Article  CAS  PubMed  Google Scholar 

  129. Ramos B, Baglietto-Vargas D, del Rio JC, Moreno-Gonzalez I, Santa-Maria C, Jimenez S, et al. Early neuropathology of somatostatin/NPY GABAergic cells in the Hippocampus of a PS1xAPP transgenic model of Alzheimer’s disease. Neurobiol Aging 2006, 27: 1658–1672.

    Article  CAS  PubMed  Google Scholar 

  130. Zallo F, Gardenal E, Verkhratsky A, Rodríguez JJ. Loss of calretinin and parvalbumin positive interneurones in the hippocampal CA1 of aged Alzheimer’s disease mice. Neurosci Lett 2018, 681: 19–25.

    Article  CAS  PubMed  Google Scholar 

  131. Nykänen NP, Kysenius K, Sakha P, Tammela P, Huttunen HJ. Γ-Aminobutyric acid type A (GABAA) receptor activation modulates tau phosphorylation. J Biol Chem 2012, 287: 6743–6752.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Nilsen LH, Rae C, Ittner LM, Götz J, Sonnewald U. Glutamate metabolism is impaired in transgenic mice with tau hyperphosphorylation. J Cereb Blood Flow Metab 2013, 33: 684–691.

    Article  PubMed  CAS  Google Scholar 

  133. Hazra A, Gu F, Aulakh A, Berridge C, Eriksen JL, Ziburkus J. Inhibitory neuron and hippocampal circuit dysfunction in an aged mouse model of Alzheimer’s disease. PLoS ONE 2013, 8: e64318. https://doi.org/10.1371/journal.pone.0064318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zheng J, Li HL, Tian N, Liu F, Wang L, Yin YL, et al. Interneuron accumulation of phosphorylated tau impairs adult hippocampal neurogenesis by suppressing GABAergic transmission. Cell Stem Cell 2020, 26: 462–466.

    Article  CAS  PubMed  Google Scholar 

  135. Yang X, Yao C, Tian T, Li X, Yan H, Wu J, et al. A novel mechanism of memory loss in Alzheimer’s disease mice via the degeneration of entorhinal-CA1 synapses. Mol Psychiatry 2018, 23: 199–210.

    Article  CAS  PubMed  Google Scholar 

  136. Bienvenu TC, Busti D, Magill PJ, Ferraguti F, Capogna M. Cell-type-specific recruitment of amygdala interneurons to hippocampal Theta rhythm and noxious stimuli in vivo. Neuron 2012, 74: 1059–1074.

    Article  CAS  PubMed  Google Scholar 

  137. Loreth D, Ozmen L, Revel FG, Knoflach F, Wetzel P, Frotscher M, et al. Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy. Neurobiol Dis 2012, 47: 1–12.

    Article  CAS  PubMed  Google Scholar 

  138. Wang Y, Romani S, Lustig B, Leonardo A, Pastalkova E. Theta sequences are essential for internally generated hippocampal firing fields. Nat Neurosci 2015, 18: 282–288.

    Article  CAS  PubMed  Google Scholar 

  139. Wikenheiser AM, Redish AD. Hippocampal Theta sequences reflect current goals. Nat Neurosci 2015, 18: 289–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cheng JH, Ji DY. Rigid firing sequences undermine spatial memory codes in a neurodegenerative mouse model. Elife 2013, 2: e00647. https://doi.org/10.7554/eLife.00647.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Villette V, Poindessous-Jazat F, Simon A, Léna C, Roullot E, Bellessort B, et al. Decreased rhythmic GABAergic septal activity and memory-associated Theta oscillations after hippocampal amyloid-beta pathology in the rat. J Neurosci 2010, 30: 10991–11003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, et al. Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated pathology and improves cognition. Cell 2019, 177: 256-271.e22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Jun H, Bramian A, Soma S, Saito T, Saido TC, Igarashi KM. Disrupted place cell remapping and impaired grid cells in a knockin model of Alzheimer’s disease. Neuron 2020, 107: 1095-1112.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Herrmann CS, Demiralp T. Human EEG gamma oscillations in neuropsychiatric disorders. Clin Neurophysiol 2005, 116: 2719–2733.

    Article  CAS  PubMed  Google Scholar 

  145. Yamamoto J, Suh J, Takeuchi D, Tonegawa S. Successful execution of working memory linked to synchronized high-frequency gamma oscillations. Cell 2014, 157: 845–857.

    Article  CAS  PubMed  Google Scholar 

  146. Mikulovic S, Restrepo CE, Siwani S, Bauer P, Pupe S, Tort ABL, et al. Ventral hippocampal OLM cells control type 2 Theta oscillations and response to predator odor. Nat Commun 2018, 9: 3638.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, et al. Author Correction: Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 2018, 562: E1. https://doi.org/10.1038/s41586-018-0351-4.

    Article  CAS  PubMed  Google Scholar 

  148. Huh CY, Amilhon B, Ferguson KA, Manseau F, Torres-Platas SG, Peach JP, et al. Excitatory inputs determine phase-locking strength and spike-timing of CA1 stratum Oriens/Alveus parvalbumin and somatostatin interneurons during intrinsically generated hippocampal Theta rhythm. J Neurosci 2016, 36: 6605–6622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Etter G, van der Veldt S, Manseau F, Zarrinkoub I, Trillaud-Doppia E, Williams S. Optogenetic gamma stimulation rescues memory impairments in an Alzheimer’s disease mouse model. Nat Commun 2019, 10: 5322.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Chung H, Park K, Jang HJ, Kohl MM, Kwag J. Dissociation of somatostatin and parvalbumin interneurons circuit dysfunctions underlying hippocampal Theta and gamma oscillations impaired by amyloid β oligomers in vivo. Brain Struct Funct 2020, 225: 935–954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Mesulam MM. The cholinergic innervation of the human cerebral cortex. Prog Brain Res 2004, 145: 67–78.

    Article  PubMed  Google Scholar 

  152. Wilcock GK, Esiri MM, Bowen DM, Smith CC. Alzheimer’s disease. Correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities. J Neurol Sci 1990, 57: 407–417.

    Article  Google Scholar 

  153. Kooi EJ, Prins M, Bajic N, Beliën JA, Gerritsen WH, van Horssen J, et al. Cholinergic imbalance in the multiple sclerosis Hippocampus. Acta Neuropathol 2011, 122: 313–322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Yoon SY, Choi JU, Cho MH, Yang KM, Ha H, Chung IJ, et al. Α-secretase cleaved amyloid precursor protein (APP) accumulates in cholinergic dystrophic neurites in normal, aged Hippocampus. Neuropathol Appl Neurobiol 2013, 39: 800–816.

    Article  CAS  PubMed  Google Scholar 

  155. Fang LQ, Duan JJ, Ran DZ, Fan ZH, Yan Y, Huang NY, et al. Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila. Neurosci Bull 2012, 28: 585–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Berger-Sweeney J, Stearns NA, Murg SL, Floerke-Nashner LR, Lappi DA, Baxter MG. Selective immunolesions of cholinergic neurons in mice: Effects on neuroanatomy, neurochemistry, and behavior. J Neurosci 2001, 21: 8164–8173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Lai MK, Tsang SW, Alder JT, Keene J, Hope T, Esiri MM, et al. Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease. Psychopharmacology (Berl) 2005, 179: 673–677.

    Article  CAS  Google Scholar 

  158. Lai MK, Tsang SW, Francis PT, Keene J, Hope T, Esiri MM, et al. Postmortem serotoninergic correlates of cognitive decline in Alzheimer’s disease. Neuroreport 2002, 13: 1175–1178.

    Article  CAS  PubMed  Google Scholar 

  159. Yamamoto T, Hirano A. Nucleus raphe dorsalis in Alzheimer’s disease: Neurofibrillary tangles and loss of large neurons. Ann Neurol 1985, 17: 573–577.

    Article  CAS  PubMed  Google Scholar 

  160. Mowla A, Mosavinasab M, Haghshenas H, Borhani Haghighi A. Does serotonin augmentation have any effect on cognition and activities of daily living in Alzheimer’s dementia? A double-blind, placebo-controlled clinical trial. J Clin Psychopharmacol 2007, 27: 484–487.

    Article  CAS  PubMed  Google Scholar 

  161. Mokler DJ, Lariviere D, Johnson DW, Theriault NL, Bronzino JD, Dixon M, et al. Serotonin neuronal release from dorsal Hippocampus following electrical stimulation of the dorsal and Median raphé nuclei in conscious rats. Hippocampus 1998, 8: 262–273.

    Article  CAS  PubMed  Google Scholar 

  162. Yoshida K, Drew MR, Mimura M, Tanaka KF. Serotonin-mediated inhibition of ventral Hippocampus is required for sustained goal-directed behavior. Nat Neurosci 2019, 22: 770–777.

    Article  CAS  PubMed  Google Scholar 

  163. Abela AR, Browne CJ, Sargin D, Prevot TD, Ji XD, Li Z, et al. Median raphe serotonin neurons promote anxiety-like behavior via inputs to the dorsal Hippocampus. Neuropharmacology 2020, 168: 107985.

    Article  CAS  PubMed  Google Scholar 

  164. Teixeira CM, Rosen ZB, Suri D, Sun Q, Hersh M, Sargin D, et al. Hippocampal 5-HT input regulates memory formation and schaffer collateral excitation. Neuron 2018, 98: 992-1004.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This review was supported by Grants from the Natural Science Foundation of China (31730035, 82071219, 91632305, and 91949205), the Ministry of Science and Technology of China (2016YFC1305800), and the Guangdong Provincial Key S&T Program (2018B030336001).

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  1. Department of Pathophysiology, School of Basic Medicine, Ministry of Education Key Laboratory for Neurological Disorders, Hubei Key Laboratory for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Yang Ying & Jian-Zhi Wang

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Ying, Y., Wang, JZ. Illuminating Neural Circuits in Alzheimer’s Disease. Neurosci. Bull. 37, 1203–1217 (2021). https://doi.org/10.1007/s12264-021-00716-6

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