Login Register Cart 0
Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
General Research Article

Amyloid-beta Induced Neurotoxicity Impairs Cognition and Adult Hippocampal Neurogenesis in a Mouse Model for Alzheimer’s Disease

Author(s): Sanila Amber, Sumera, Fatima J. Mirza, Muhammad Asif , Deeba Hassan, Touqeer Ahmed and Saadia Zahid*

Volume 17, Issue 11, 2020

Page: [1033 - 1042] Pages: 10

DOI: 10.2174/1567205017666201224162730

Price: $65

Abstract

Background: Neurogenesis, the key mechanism to generate new neurons from existing stem cell niches continues throughout the life in the adult mammalian brain, although decelerate with aging or the progression of neurodegenerative disorders like Alzheimer’s disease (AD). In the past few years, impaired adult hippocampal neurogenesis emerged as a contributing hallmark of AD pathophysiology along with amyloid beta (Aβ) and tau hyper phosphorylation-induced neurotoxicity. However, no conclusive evidence exists that indicates the up/down-regulation of adult hippocampal neurogenesis during the course of AD progression.

Methods: In this study, we examined alterations in adult hippocampal neurogenesis and cognitive deficits using Aβ(1-42)-induced mouse model of AD.

Results: Our results demonstrate that Aβ administration induces an anxiety like behavior and impairs spatial and non-spatial memory and learning in BALB/c mice. Extensive neuronal loss was also evident in the dentate gyrus (DG), CA1, CA2 and CA3 regions of hippocampus in Aβ-treated animals. Furthermore, Aβ-exposure markedly reduced the real-time expression of markers of cell proliferation and migration i.e. Ki67 and DCX, whereas immunohistochemistry analysis revealed a substantial reduction in the expression levels of Ki67 and NeuN.

Conclusion: Our findings highlight the association of Aβ-induced neurotoxicity with altered neurogenesis and memory formation; however further insight is warranted to explore the underlying molecular pathway(s). Moreover, the treatment strategies aiming to repair the adult hippocampal neurogenesis hold potential as AD therapeutics.

Keywords: Hippocampus, neurodegeneration, neurogenesis, Alzheimer's disease, cognition, neurotoxicity.

« Previous Next »
[1]
Ashe KH, Zahs KR. Probing the biology of Alzheimer’s disease in mice. Neuron 2010; 66(5): 631-45.
[http://dx.doi.org/10.1016/j.neuron.2010.04.031] [PMID: 20547123]
[2]
Yankner BA. Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron 1996; 16(5): 921-32.
[http://dx.doi.org/10.1016/S0896-6273(00)80115-4] [PMID: 8630250]
[3]
Braak H, Braak E, Bohl J. Staging of Alzheimer-related cortical destruction. Eur Neurol 1993; 33(6): 403-8.
[http://dx.doi.org/10.1159/000116984] [PMID: 8307060]
[4]
Nitta A, Fukuta T, Hasegawa T, Nabeshima T. Continuous infusion of β-amyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration. Jpn J Pharmacol 1997; 73(1): 51-7.
[http://dx.doi.org/10.1254/jjp.73.51] [PMID: 9032134]
[5]
Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996; 274(5284): 99-102.
[http://dx.doi.org/10.1126/science.274.5284.99] [PMID: 8810256]
[6]
Haughey NJ, Liu D, Nath A, Borchard AC, Mattson MP. Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid β-peptide: implications for the pathogenesis of Alzheimer’s disease. Neuromolecular Med 2002; 1(2): 125-35.
[http://dx.doi.org/10.1385/NMM:1:2:125] [PMID: 12025858]
[7]
Kempermann G, Song H, Gage FH. Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 2015; 7(9)a018812
[http://dx.doi.org/10.1101/cshperspect.a018812] [PMID: 26330519]
[8]
Sahay A, Scobie KN, Hill AS, et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 2011; 472(7344): 466-70.
[http://dx.doi.org/10.1038/nature09817] [PMID: 21460835]
[9]
Stone SS, Teixeira CM, Devito LM, et al. Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J Neurosci 2011; 31(38): 13469-84.
[http://dx.doi.org/10.1523/JNEUROSCI.3100-11.2011] [PMID: 21940440]
[10]
Clelland CD, Choi M, Romberg C, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 2009; 325(5937): 210-3.
[http://dx.doi.org/10.1126/science.1173215] [PMID: 19590004]
[11]
Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H. When neurogenesis encounters aging and disease. Trends Neurosci 2010; 33(12): 569-79.
[http://dx.doi.org/10.1016/j.tins.2010.09.003] [PMID: 20961627]
[12]
Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG. Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 2004; 127(3): 601-9.
[http://dx.doi.org/10.1016/j.neuroscience.2004.05.040] [PMID: 15283960]
[13]
Jin K, Galvan V, Xie L, et al. Enhanced neurogenesis in Alzheimer’s disease transgenic (PDGF-APPSw,Ind) mice. Proc Natl Acad Sci USA 2004; 101(36): 13363-7.
[http://dx.doi.org/10.1073/pnas.0403678101] [PMID: 15340159]
[14]
Jin K, Peel AL, Mao XO, et al. Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci USA 2004; 101(1): 343-7. [b
[http://dx.doi.org/10.1073/pnas.2634794100] [PMID: 14660786]
[15]
Li B, Yamamori H, Tatebayashi Y, et al. Failure of neuronal maturation in Alzheimer disease dentate gyrus. J Neuropathol Exp Neurol 2008; 67(1): 78-84.
[http://dx.doi.org/10.1097/nen.0b013e318160c5db] [PMID: 18091557]
[16]
Martinez-Canabal A, Wheeler AL, Sarkis D, et al. Chronic over-expression of TGFβ1 alters hippocampal structure and causes learning deficits. Hippocampus 2013; 23(12): 1198-211.
[http://dx.doi.org/10.1002/hipo.22159] [PMID: 23804429]
[17]
Ermini FV, Grathwohl S, Radde R, et al. Neurogenesis and alterations of neural stem cells in mouse models of cerebral amyloidosis. Am J Pathol 2008; 172(6): 1520-8.
[http://dx.doi.org/10.2353/ajpath.2008.060520] [PMID: 18467698]
[18]
Winner B, Kohl Z, Gage FH. Neurodegenerative disease and adult neurogenesis. Eur J Neurosci 2011; 33(6): 1139-51.
[http://dx.doi.org/10.1111/j.1460-9568.2011.07613.x] [PMID: 21395858]
[19]
Lazarov O, Marr RA. Neurogenesis and Alzheimer’s disease: at the crossroads. Exp Neurol 2010; 223(2): 267-81.
[http://dx.doi.org/10.1016/j.expneurol.2009.08.009] [PMID: 19699201]
[20]
Ahmad A, Ali T, Park HY, Badshah H, Rehman SU, Kim MO. Neuroprotective effect of fisetin against amyloid-beta-induced cognitive/synaptic dysfunction, neuroinflammation, and neurodegeneration in adult mice. Mol Neurobiol 2017; 54(3): 2269-85.
[http://dx.doi.org/10.1007/s12035-016-9795-4] [PMID: 26944285]
[21]
Kong LN, Zuo PP, Mu L, Liu YY, Yang N. Gene expression profile of amyloid beta protein-injected mouse model for Alzheimer disease. Acta Pharmacol Sin 2005; 26(6): 666-72.
[http://dx.doi.org/10.1111/j.1745-7254.2005.00129.x] [PMID: 15916731]
[22]
van der Stelt M, Mazzola C, Esposito G, et al. Endocannabinoids and β-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels. Cell Mol Life Sci 2006; 63(12): 1410-24.
[http://dx.doi.org/10.1007/s00018-006-6037-3] [PMID: 16732431]
[23]
Cetin F, Dincer S. The effect of intrahippocampal beta amyloid (1-42) peptide injection on oxidant and antioxidant status in rat brain. Ann N Y Acad Sci 2007; 1100: 510-7.
[http://dx.doi.org/10.1196/annals.1395.056] [PMID: 17460216]
[24]
Daher F, Mattioli R. Impairment in the aversive memory of mice in the inhibitory avoidance task but not in the elevated plus maze through intra-amygdala injections of histamine. Pharmacol Biochem Behav 2015; 135: 237-45.
[http://dx.doi.org/10.1016/j.pbb.2015.05.023] [PMID: 26079070]
[25]
Farhat SM, Mahboob A, Iqbal G, Ahmed T. Aluminum-induced cholinergic deficits in different brain parts and its implications on sociability and cognitive functions in mouse. Biol Trace Elem Res 2017; 177(1): 115-21.
[http://dx.doi.org/10.1007/s12011-016-0856-3] [PMID: 27709498]
[26]
Bromley-Brits K, Deng Y, Song W. Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J Vis Exp 2011; 53(53)e2920
[http://dx.doi.org/10.3791/2920] [PMID: 21808223]
[27]
Roher AE, Esh CL, Kokjohn TA, et al. Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer’s disease. Alzheimers Dement 2009; 5(1): 18-29.
[http://dx.doi.org/10.1016/j.jalz.2008.10.004] [PMID: 19118806]
[28]
Hellstrom-Lindahl E, Viitanen M, Marutle A. Comparison of Aβ levels in the brain of Swedish APP670, 671 and PS1M146V mutation carriers and patients with sporadic Alzheimer’s disease. Neurochem Int 2009; 55: 243-52.
[http://dx.doi.org/10.1016/j.neuint.2009.03.007] [PMID: 19524115]
[29]
Ali T, Kim MO. Melatonin ameliorates amyloid beta-induced memory deficits, tau hyperphosphorylation and neurodegeneration via PI3/Akt/GSk3β pathway in the mouse hippocampus. J Pineal Res 2015; 59(1): 47-59.
[http://dx.doi.org/10.1111/jpi.12238] [PMID: 25858697]
[30]
Li J, Bao L, Zha D, et al. Oridonin protects against the inflammatory response in diabetic nephropathy by inhibiting the TLR4/p38-MAPK and TLR4/NF-κB signaling pathways. Int Immunopharmacol 2018; 55: 9-19.
[http://dx.doi.org/10.1016/j.intimp.2017.11.040] [PMID: 29207360]
[31]
Qi Y, Shang L, Liao Z, et al. Intracerebroventricular injection of resveratrol ameliorated Aβ-induced learning and cognitive decline in mice. Metab Brain Dis 2019; 34(1): 257-66.
[http://dx.doi.org/10.1007/s11011-018-0348-6] [PMID: 30460524]
[32]
Singh A, Kumar A. .Comparative analysis of intrahippocampal amyloid beta (1–42) and it is intracerebroventricular streptozotocin models of Alzheimer’s disease: possible behavioral, biochemical, mitochondrial, cellular and histopathological evidences. J Alzheimers Dis Parkinsonism 2016; 6: 2161-0460..
[http://dx.doi.org/10.4172/2161-0460.1000208]
[33]
Yun HM, Kim HS, Park KR, et al. Placenta-derived mesenchymal stem cells improve memory dysfunction in an Aβ1-42-infused mouse model of Alzheimer’s disease. Cell Death Dis 2013; 4e958
[http://dx.doi.org/10.1038/cddis.2013.490] [PMID: 24336078]
[34]
Buckmaster CA, Eichenbaum H, Amaral DG, Suzuki WA, Rapp PR. Entorhinal cortex lesions disrupt the relational organization of memory in monkeys. J Neurosci 2004; 24(44): 9811-25.
[http://dx.doi.org/10.1523/JNEUROSCI.1532-04.2004] [PMID: 15525766]
[35]
Clark RE, Zola SM, Squire LR. Impaired recognition memory in rats after damage to the hippocampus. J Neurosci 2000; 20(23): 8853-60.
[http://dx.doi.org/10.1523/JNEUROSCI.20-23-08853.2000] [PMID: 11102494]
[36]
Hammond RS, Tull LE, Stackman RW. On the delay-dependent involvement of the hippocampus in object recognition memory. Neurobiol Learn Mem 2004; 82(1): 26-34.
[http://dx.doi.org/10.1016/j.nlm.2004.03.005] [PMID: 15183168]
[37]
Ennaceur A. One-trial object recognition in rats and mice: methodological and theoretical issues. Behav Brain Res 2010; 215(2): 244-54.
[http://dx.doi.org/10.1016/j.bbr.2009.12.036] [PMID: 20060020]
[38]
Tucci P, Mhillaj E, Morgese MG, et al. Memantine prevents memory consolidation failure induced by soluble beta amyloid in rats. Front Behav Neurosci 2014; 8: 332.
[http://dx.doi.org/10.3389/fnbeh.2014.00332] [PMID: 25285073]
[39]
Prado Lima MG, Schimidt HL, Garcia A, et al. Environmental enrichment and exercise are better than social enrichment to reduce memory deficits in amyloid beta neurotoxicity. Proc Natl Acad Sci USA 2018; 115(10): E2403-9.
[http://dx.doi.org/10.1073/pnas.1718435115] [PMID: 29463708]
[40]
Cioanca O, Hritcu L, Mihasan M, Trifan A, Hancianu M. Inhalation of coriander volatile oil increased anxiolytic–antidepressant-like behaviors and decreased oxidative status in beta-amyloid (1–42) rat model of Alzheimer's disease. Physiol behave 2014; 131: 68-74..
[41]
Gupta A, Goyal R. Amyloid beta plaque: a culprit for neurodegeneration. Acta Neurol Belg 2016; 116(4): 445-50.
[http://dx.doi.org/10.1007/s13760-016-0639-9] [PMID: 27118573]
[42]
Maltsev AV, Bystryak S, Galzitskaya OV. The role of β-amyloid peptide in neurodegenerative diseases. Ageing Res Rev 2011; 10(4): 440-52.
[http://dx.doi.org/10.1016/j.arr.2011.03.002] [PMID: 21406255]
[43]
Kempermann G, Gast D, Gage FH. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol 2002; 52(2): 135-43.
[http://dx.doi.org/10.1002/ana.10262] [PMID: 12210782]
[44]
Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. Neurogenesis in the adult is involved in the formation of trace memories. Nature 2001; 410(6826): 372-6.
[http://dx.doi.org/10.1038/35066584] [PMID: 11268214]
[45]
Pascoe MC, Howells DW, Crewther DP, Carey LM, Crewther SG. Fish oil supplementation associated with decreased cellular degeneration and increased cellular proliferation 6 weeks after middle cerebral artery occlusion in the rat. Neuropsychiatr Dis Treat 2015; 11: 153-64.
[http://dx.doi.org/10.2147/NDT.S72925] [PMID: 25609971]
[46]
Oh SH, Kim HN, Park HJ, Shin JY, Lee PH. Mesenchymal stem cells increase hippocampal neurogenesis and neuronal differentiation by enhancing the wnt signaling pathway in an Alzheimer’s disease model. Cell Transplant 2015; 24(6): 1097-109.
[http://dx.doi.org/10.3727/096368914X679237] [PMID: 24612635]
[47]
Kim BK, Shin MS, Kim CJ, Baek SB, Ko YC, Kim YP. Treadmill exercise improves short-term memory by enhancing neurogenesis in amyloid beta-induced Alzheimer disease rats. J Exerc Rehabil 2014; 10(1): 2-8.
[http://dx.doi.org/10.12965/jer.140086] [PMID: 24678498]
[48]
Wang Q, Xu Z, Tang J, et al. Voluntary exercise counteracts Aβ25-35-induced memory impairment in mice. Behav Brain Res 2013; 256: 618-25.
[http://dx.doi.org/10.1016/j.bbr.2013.09.024] [PMID: 24055357]
[49]
Verret L, Jankowsky JL, Xu GM, Borchelt DR, Rampon C. Alzheimer’s-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J Neurosci 2007; 27(25): 6771-80.
[http://dx.doi.org/10.1523/JNEUROSCI.5564-06.2007] [PMID: 17581964]
[50]
Zhang C, McNeil E, Dressler L, Siman R. Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer’s disease. Exp Neurol 2007; 204(1): 77-87.
[http://dx.doi.org/10.1016/j.expneurol.2006.09.018] [PMID: 17070803]
[51]
Bolos M, Spuch C, Ordoñez-Gutierrez L, Wandosell F, Ferrer I, Carro E. Neurogenic effects of β-amyloid in the choroid plexus epithelial cells in Alzheimer’s disease. Cell Mol Life Sci 2013; 70(15): 2787-97.
[http://dx.doi.org/10.1007/s00018-013-1300-x] [PMID: 23455075]
[52]
Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 2012; 13(4): 227-32.
[http://dx.doi.org/10.1038/nrg3185] [PMID: 22411467]
[53]
Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med 2019; 25(4): 554-60.
[http://dx.doi.org/10.1038/s41591-019-0375-9] [PMID: 30911133]
[54]
Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ. Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer’s disease. J Comp Neurol 2006; 495(1): 70-83.
[http://dx.doi.org/10.1002/cne.20840] [PMID: 16432899]
[55]
López-Toledano MA, Shelanski ML. Increased neurogenesis in young transgenic mice overexpressing human APP(Sw, Ind). J Alzheimers Dis 2007; 12(3): 229-40.
[http://dx.doi.org/10.3233/JAD-2007-12304] [PMID: 18057556]
[56]
Gan L, Qiao S, Lan X, et al. Neurogenic responses to amyloid-beta plaques in the brain of Alzheimer’s disease-like transgenic (pPDGF-APPSw,Ind) mice. Neurobiol Dis 2008; 29(1): 71-80.
[http://dx.doi.org/10.1016/j.nbd.2007.08.002] [PMID: 17916429]
[57]
Mirochnic S, Wolf S, Staufenbiel M, Kempermann G. Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease. Hippocampus 2009; 19(10): 1008-18.
[http://dx.doi.org/10.1002/hipo.20560] [PMID: 19219917]
[58]
He N, Jin WL, Lok KH, Wang Y, Yin M, Wang ZJ. Amyloid-β(1-42) oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2. Cell Death Dis 2013; 4e924
[http://dx.doi.org/10.1038/cddis.2013.437] [PMID: 24263098]
[59]
Sun P, Knezovic A, Parlak M, et al. Long-term effects of intracerebroventricular streptozotocin treatment on adult neurogenesis in the rat hippocampus. Curr Alzheimer Res 2015; 12(8): 772-84.
[http://dx.doi.org/10.2174/1567205012666150710112147] [PMID: 26159196]
[60]
Sotthibundhu A, Li QX, Thangnipon W, Coulson EJ. Abeta(1-42) stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor. Neurobiol Aging 2009; 30(12): 1975-85.
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.02.004] [PMID: 18374455]
[61]
Russo I, Caracciolo L, Tweedie D, et al. 3,6′-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit. J Neurochem 2012; 122(6): 1181-92.
[http://dx.doi.org/10.1111/j.1471-4159.2012.07846.x] [PMID: 22731394]
[62]
Zheng JY, Liang KS, Wang XJ, Zhou XY, Sun J, Zhou SN. Chronic estradiol administration during the early stage of Alzheimer’s disease pathology rescues adult hippocampal neurogenesis and ameliorates cognitive deficits in Aβ1-42 mice. Mol Neurobiol 2017; 54(10): 7656-69.
[http://dx.doi.org/10.1007/s12035-016-0181-z] [PMID: 27838872]
[63]
Marlatt MW, Lucassen PJ. Neurogenesis and Alzheimer’s disease: biology and pathophysiology in mice and men. Curr Alzheimer Res 2010; 7(2): 113-25.
[http://dx.doi.org/10.2174/156720510790691362] [PMID: 19860727]
[64]
Rodríguez JJ, Noristani HN, Olabarria M, et al. Voluntary running and environmental enrichment restores impaired hippocampal neurogenesis in a triple transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res 2011; 8(7): 707-17.
[http://dx.doi.org/10.2174/156720511797633214] [PMID: 21453244]
[65]
Herran E, Perez-Gonzalez R, Igartua M, Pedraz JL, Carro E, Hernandez RM. Enhanced hippocampal neurogenesis in APP/Ps1 mouse model of Alzheimer’s disease after implantation of VEGF-loaded PLGA nanospheres. Curr Alzheimer Res 2015; 12(10): 932-40.
[http://dx.doi.org/10.2174/1567205012666151027121622] [PMID: 26502822]
[66]
Dupret D, Revest JM, Koehl M, et al. Spatial relational memory requires hippocampal adult neurogenesis. PLoS One 2008; 3(4)e1959
[http://dx.doi.org/10.1371/journal.pone.0001959 ] [PMID: 18509506]

Rights & Permissions Print Cite
Article Metrics
23
© 2024 Bentham Science Publishers | Privacy Policy