Proteomics Analysis of CA1 Region of the Hippocampus in Pre-, Progression and Pathological Stages in a Mouse Model of the Alzheimer’s Disease

Author(s): Busra Gurel, Mehmet Cansev, Cansu Koc, Busra Ocalan, Aysen Cakir, Sami Aydin, Nevzat Kahveci, Ismail Hakki Ulus, Betul Sahin, Merve Karayel Basar, Ahmet Tarik Baykal*

Journal Name: Current Alzheimer Research

Volume 16 , Issue 7 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


Background: CA1 subregion of the hippocampal formation is one of the primarily affected structures in AD, yet not much is known about proteome alterations in the extracellular milieu of this region.

Objective: In this study, we aimed to identify the protein expression alterations throughout the pre-pathological, progression and pathological stages of AD mouse model.

Methods: The CA1 region perfusates were collected by in-vivo intracerebral push-pull perfusion from transgenic 5XFAD mice and their non-transgenic littermates at 3, 6 and 12 wereβmonths of age. Morris water maze test and immunohistochemistry staining of A performed to determine the stages of the disease in this mouse model. The protein expression differences were analyzed by label-free shotgun proteomics analysis.

Results: A total of 251, 213 and 238 proteins were identified in samples obtained from CA1 regions of mice at 3, 6 and 12 months of age, respectively. Of these, 68, 41 and 33 proteins showed statistical significance. Pathway analysis based on the unique and common proteins within the groups revealed that several pathways are dysregulated during different stages of AD. The alterations in glucose and lipid metabolisms respectively in pre-pathologic and progression stages of the disease, lead to imbalances in ROS production via diminished SOD level and impairment of neuronal integrity.

Conclusion: We conclude that CA1 region-specific proteomic analysis of hippocampal degeneration may be useful in identifying the earliest as well as progressional changes that are associated with Alzheimer’s disease.

Keywords: Alzheimer's disease, CA1, proteomics, 5XFAD, Aβ plaques, cerebral cortex.

Morishima-Kawashima M, Ihara Y. Alzheimer’s disease: beta-Amyloid protein and tau. J Neurosci Res 70(3): 392-401. (2002)
[] [PMID: 12391602]
Teter B, Ashford JW. Neuroplasticity in Alzheimer’s disease. J Neurosci Res 70(3): 402-37. (2002)
[] [PMID: 12391603]
Mesulam MM. A plasticity-based theory of the pathogenesis of Alzheimer’s disease. Ann N Y Acad Sci 924: 42-52(2000).
[] [PMID: 11193801]
Walsh TJ, Opello KD. Neuroplasticity, the aging brain, and Alzheimer’s disease. Neurotoxicology 13(1): 101-110(1992).
[PMID: 1508410]
Parihar MS, Hemnani T. Alzheimer’s disease pathogenesis and therapeutic interventions. J Clin Neurosci 11(5): 456-67. (2004)
[] [PMID: 15177383]
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4): 239-259(1991).
[] [PMID: 1759558]
Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16: 271-278(1995).Available:
Nakazawa K, Sun LD, Quirk MC, Rondi-Reig L, Wilson MA, Tonegawa S. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38(2): 305-315(2003). Available:
[] [PMID: 12718863]
O’Reilly RC, Rudy JW. Conjunctive representations in learning and memory: principles of cortical and hippocampal function. Psychol Rev 108(2): 311-(2001).Available:
[] [PMID: 11381832]
Golby A, Silverberg G, Race E, et al. Memory encoding in Alzheimer’s disease: an fMRI study of explicit and implicit memory. Brain 128(Pt 4): 773-87. (2005)
[] [PMID: 15705615]
Schultz C, Engelhardt M. Anatomy of the hippocampal formation. Front Neurol Neurosci 34: 6-17. (2014)
[] [PMID: 24777126]
Reed JM, Squire LR. Impaired recognition memory in patients with lesions limited to the hippocampal formation. Behav Neurosci 111(4): 667-675(1997). Available:
[] [PMID: 9267644]
Bäckman L, Small BJ, Fratiglioni L. Stability of the preclinical episodic memory deficit in Alzheimer’s disease. Brain 124(Pt 1): 96-102(2001). Available:
[] [PMID: 11133790]
Buckmaster CA, Eichenbaum H, Amaral DG, Suzuki WA, Rapp PR. Entorhinal cortex lesions disrupt the relational organization of memory in monkeys. J Neurosci 24(44): 9811-25. (2004)
[] [PMID: 15525766]
Flood DG, Coleman PD. Hippocampal plasticity in normal aging and decreased plasticity in Alzheimer’s disease.Prog Brain Res 83: 435 (1990). Available:
Simonian NA, Hyman BT. Functional alterations in neural circuits in Alzheimer’s disease. Neurobiol Aging 16: 305-309(1995). Available:
Iacono D, O’Brien R, Resnick SM, Zonderman AB, Pletnikova O, Rudow G, et al. Neuronal hypertrophy in asymptomatic Alzheimer disease. J Neuropathol Exp Neurol 67(6): 578-89. (2008)
[] [PMID: 18520776]
Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68(18): 1501-8. (2007)
[] [PMID: 17470753]
Klein JB, Gozal D, Pierce WM, Thongboonkerd V, Scherzer JA. Guosz, et al. Proteomic identification of a novel protein regulated in CA1 and CA3 hippocampal regions during intermittent hypoxia. Respir Physiol Neurobiol 136(2-3): 91-103.(2003). Available: pubmed/12853002
[] [PMID: 12853002]
Corti V, Sanchez-Ruiz Y, Piccoli G, Bergamaschi A, Cannistraci CV, Pattini L, et al. Protein fingerprints of cultured CA3-CA1 hippocampal neurons: comparative analysis of the distribution of synaptosomal and cytosolic proteins. BMC Neurosci 9: 36. (2008)
[] [PMID: 18402664]
Sahara S, Yamashima T. Calpain-mediated Hsp70.1 cleavage in hippocampal CA1 neuronal death. Biochem Biophys Res Commun 393(4): 806-11. (2010)
[] [PMID: 20171158]
Wang Q, Woltjer RL, Cimino PJ, Pan C, Montine KS, Zhang J, et al. Proteomic analysis of neurofibrillary tangles in Alzheimer disease identifies GAPDH as a detergent-insoluble paired helical filament tau binding protein. FASEB J 19(7): 869-71. (2005)
[] [PMID: 15746184]
Hondius DC, van Nierop P, Li KW, Hoozemans JJ, van der Schors RC, van Haastert ES, et al. Profiling the human hippocampal proteome at all pathologic stages of Alzheimer’s disease. Alzheimers Dement 12(6): 654-68. (2016)
[] [PMID: 26772638]
Schrötter A, Oberhaus A, Kolbe K, Seger S, Mastalski T, El Magraoui F, et al. LMD proteomics provides evidence for hippocampus field-specific motor protein abundance changes with relevance to Alzheimer’s disease. Biochim Biophys Acta Proteins Proteomics 1865(6): 703-14. (2017)
[] [PMID: 28377147]
Gurel B, Cansev M, Sevinc C, Kelestemur S, Ocalan B, Causir A, et al. Early Stage Alterations in CA1 Extracellular region proteins indicate dysregulation of il6 and iron homeostasis in the 5xfad alzheimer’s disease mouse model. J Alzheimers Dis 61(4): 1399-410. (2018)
[] [PMID: 29376847]
Beker MC, Caglayan B, Yalcin E, Caglayan AB, Turkseven S, Gurel B, et al. Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT. Mol Neurobiol 55(3): 2565-76. (2018)
[] [PMID: 28421530]
Yerlikaya A, Okur E, Baykal AT, Acılan C, Boyacı I, Ulukaya E. A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line. J Proteomics 113: 315-25. (2015)
[] [PMID: 25305590]
Acioglu C, Mirabelli E, Baykal AT, Ni L, Ratnayake A, Heary RF, et al. Toll like receptor 9 antagonism modulates spinal cord neuronal function and survival: Direct versus astrocyte-mediated mechanisms. Brain Behav Immun 56: 310-24. (2016)
[] [PMID: 27044334]
Chang RY, Nouwens AS, Dodd PR, Etheridge N. The synaptic proteome in Alzheimer’s disease. Alzheimers Dement 9(5): 499-511. (2013)
[] [PMID: 23154051]
Bros P, Delatour V, Vialaret J, Lalere B, Barthelemy N, Gabelle A, et al. Quantitative detection of amyloid-β peptides by mass spectrometry: state of the art and clinical applications. Clin Chem Lab Med 53(10): 1483-93. (2015)
[] [PMID: 25719328]
Lin Y-F, Yang M-H, Yang Y-H, Chen W-C, Lu C-Y, Peng C-F, et al. Activity-dependent neuroprotector homeobox protein level in Alzheimer’s disease in Taiwanese. Genomic Med Biomarkers. Heal Sci 4: 48-50. (2012)
Stover KR, Campbell MA, Van Winssen CM, Brown RE. Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer’s disease. Behav Brain Res 289: 29-38. (2015)
[] [PMID: 25896362]
Leskovjan AC, Kretlow A, Lanzirotti A, Barrea R, Vogt S, Miller LM. Increased brain iron coincides with early plaque formation in a mouse model of Alzheimer’s disease. Neuroimage 55(1): 32-8. (2011)
[] [PMID: 21126592]
Bourassa MW, Leskovjan AC, Tappero RV. Farquhar ER4, Colton CA5, Van Nostrand WE, et al.Elevated copper in the amyloid plaques and iron in the cortex are observed in mouse models of Alzheimer’s disease that exhibit neurodegeneration. Biomed Spectrosc Imaging 2(2): 129-39. (2013)
[] [PMID: 24926425]
Schneider F, Baldauf K, Wetzel W, Reymann KG. Behavioral and EEG changes in male 5xFAD mice. Physiol Behav 135: 25-33. (2014)
[] [PMID: 24907698]
Urano T, Tohda C. Icariin improves memory impairment in Alzheimer’s disease model mice (5xFAD) and attenuates amyloid β-induced neurite atrophy. Phytother Res 24(11): 1658-63. (2010)
[] [PMID: 21031624]
Mak E, Su L, Williams GB. Watson R3, Firbank M4, Blamire A, et al Differential atrophy of hippocampal subfields: a comparative study of dementia with lewy bodies and Alzheimer disease. Am J Geriatr Psychiatry 24(2): 136-43. (2016)
[] [PMID: 26324541]
George AJ, Holsinger RMD, McLean CA, Tan SS, Scott HS, Cardamone T, et al. Decreased phosphatidylethanolamine binding protein expression correlates with Abeta accumulation in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol Aging 27(4): 614-23. (2006)
[] [PMID: 15941609]
Maki M, Matsukawa N, Yuasa H, Otsuka Y, Yamamoto T, Akatsu H, et al. Decreased expression of hippocampal cholinergic neurostimulating peptide precursor protein mRNA in the hippocampus in Alzheimer disease. J Neuropathol Exp Neurol 61(2): 176-185(2002).Available:
[] [PMID: 11853019]
Butterfield DA, Perluigi M, Sultana R. Oxidative stress in Alzheimer’s disease brain: new insights from redox proteomics. Eur J Pharmacol 545(1): 39-50. (2006)
[] [PMID: 16860790]
Feldmann RE Jr, Maurer MH, Hunzinger C, Lewicka S, Buergers HF, Kalenka A, et al. Reduction in rat phosphatidylethanolamine binding protein-1 (PEBP1) after chronic corticosterone treatment may be paralleled by cognitive impairment: a first study. Stress 11(2): 134-47. (2008)
[] [PMID: 18311602]
Counts SE, Alldred MJ, Che S, Ginsberg SD, Mufson EJ. Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 79: 172-9. (2014)
[] [PMID: 24445080]
Tamura H, Fukada M, Fujikawa A, Noda M. Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP. Neurosci Lett 399(1-2): 33-8. (2006)
[] [PMID: 16513268]
Cressant A, Dubreuil V, Kong J, Kranz TM, Lazarini F, Launay JM, et al. Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice. Psychopharmacology (Berl) 234(4): 575-87. (2017)
[] [PMID: 28025742]
Khoonsari PE, Häggmark A, Lönnberg M, Mikus M, Kilander L, Lannfelt L, et al. Analysis of the cerebrospinal fluid proteome in alzheimer’s disease. PLoS One. Public Library Sci 11(3)e0150672 (2016)
Takeuchi T, Ohtsuki G, Yoshida T, Fukaya M, Wainai T, Yamashita M, et al. Enhancement of both long-term depression induction and optokinetic response adaptation in mice lacking delphilin.Grant SGN, editor PLoS One 3.e2297 (2008).
Matsuda K, Matsuda S, Gladding CM, Yuzaki M. Characterization of the δ2 glutamate receptor-binding protein delphilin: splicing variants with differential palmitoylation and an additional PDZ domain. J Biol Chem 281(35): 25577-87. (2006)
[] [PMID: 16835239]
Majd S, Power JHT. Oxidative stress and decreased mitochondrial superoxide dismutase 2 and peroxiredoxins 1 and 4 based mechanism of concurrent activation of AMPK and mTOR in Alzheimer’s disease. Curr Alzheimer Res 15(8): 764-76. (2018)
[] [PMID: 29473507]
Rodrigues GP, Cozzolino SMF, Marreiro DDN, Caldas DRC, da Silva KG, de Sousa Almondes KG, et al. Mineral status and superoxide dismutase enzyme activity in Alzheimer’s disease. J Trace Elem Med Biol 44: 83-7. (2017)
[] [PMID: 28965606]
Di Domenico F, Sultana R, Barone E, Perluigi M, Cini C, Mancuso C, et al. Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer’s disease subjects. J Proteomics 74(7): 1091-103. (2011)
[] [PMID: 21515431]
Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2(1)a006346 (2012)
[] [PMID: 22315714]
Gallagher JJ, Finnegan ME, Grehan B, Dobson J, Collingwood JF, Lynch MA. Modest amyloid deposition is associated with iron dysregulation, microglial activation, and oxidative stress. J Alzheimers Dis 28(1): 147-61. (2012)
[] [PMID: 21971404]
Meadowcroft MD, Connor JR, Yang QX. Cortical iron regulation and inflammatory response in Alzheimer’s disease and APPSWE/PS1ΔE9 mice: a histological perspective. Front Neurosci 9: 255. (2015)
[] [PMID: 26257600]
Milionis HJ, Florentin M, Giannopoulos S. Metabolic syndrome and Alzheimer’s disease: a link to a vascular hypothesis? CNS Spectr 13(7): 606-613(2008).Available:
[] [PMID: 18622365]
Luque-Contreras D, Carvajal K, Toral-Rios D, Franco-Bocanegra D, Campos-Peña V. Oxidative stress and metabolic syndrome: cause or consequence of Alzheimer’s disease? Oxid Med Cell Longev 2014497802 (2014)
[] [PMID: 24683436]
de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2(6): 1101-13. (2008)
[] [PMID: 19885299]
Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis 8(3): 247-68. (2005)
[] [PMID: 16340083]
Gerozissis K. Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 585(1): 38-49. (2008)
[] [PMID: 18407262]
Ying M, Sui X, Zhang Y, Sun Q, Qu Z, Luo X. Identification of Novel Key Molecules involved in spatial memory impairment in triple transgenic mice of Alzheimer’s disease. Mol Neurobiol 54(5): 3843-58. (2017)
[] [PMID: 27335030]
Wood WG, Li L, Müller WE, Eckert GP. Cholesterol as a causative factor in Alzheimer’s disease: a debatable hypothesis. J Neurochem 129(4): 559-72. (2014)
[] [PMID: 24329875]
Rojas-Gutierrez E, Muñoz-Arenas G, Treviño S, Espinosa B, Chavez R, Rojas K, et al. Alzheimer’s disease and metabolic syndrome: a link from oxidative stress and inflammation to neurodegeneration. Synapse 71(10)e21990 (2017)
[] [PMID: 28650104]
Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 66(3): 300-5. (2009)
[] [PMID: 19273747]
An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement 14(3): 318-29. (2018)
[] [PMID: 29055815]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [613 - 621]
Pages: 9
DOI: 10.2174/1567205016666190730155926
Price: $65

Article Metrics

PDF: 52
HTML: 10