Skip to main content

Advertisement

Log in

Age-related loss of noradrenergic neurons in the brains of triple transgenic mice

AGE Aims and scope Submit manuscript

Abstract

Microscopic findings in Alzheimer’s disease (AD) at autopsy include a wide cortical distribution of beta amyloid (Aβ)-containing plaques and diminished numbers of pyramidal neurons in CA1 of hippocampus and tyrosine hydroxylase-positive (TH+) neurons in the locus coeruleus (LC). To better understand the neuropathology underlying cognitive decline in AD, we analyzed the AD-type neuropathology in brains of triple transgenic (3×Tg) mice harboring mutations for APPswe, PS1M146V, and tauP301L. Histochemical and immunohistochemical staining and computerized stereology were carried out in age-matched young, early middle age, and late middle age 3×Tg mice. The 3×Tg mice showed an intracellular Aβ deposition in subiculum and CA1 pyramidal neurons and an extracellular distribution of amyloid plaques specifically in the subiculum of hippocampal formation and in neocortical layer V. The 3×Tg mice also showed an age-related loss of TH+ neurons in LC, with a loss of 37% of these neurons at 15 months of age. There was no loss of CA1 neurons at any age examined. Reduced AD-type neuropathology in CA1 of 3×Tg mice suggests a possible neuroprotective role for high intracellular-to-extracellular ratios of insoluble Aβ deposits. Understanding the neurobiology of this apparent neuroprotection could lead to an improved understanding of age-related cognitive function in general, and the development of novel strategies for the therapeutic management of AD patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  • Berg L, McKeel DW Jr, Miller JP, Storandt M, Rubin EH, Morris JC, Baty J, Coats M, Norton J, Goate AM, Price JL, Gearing M, Mirra SS, Saunders AM (1998) Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 55(3):326–335

    Article  PubMed  CAS  Google Scholar 

  • Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42(1):33–84. doi:S0165017303001437

    Article  PubMed  Google Scholar 

  • Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19(4):939–945. doi:S0896-6273(00)80974-5

    Article  PubMed  CAS  Google Scholar 

  • Busch C, Bohl J, Ohm TG (1997) Spatial, temporal and numeric analysis of Alzheimer changes in the nucleus coeruleus. Neurobiol Aging 18(4):401–406. doi:S0197-4580(97)00035-3

    Article  PubMed  CAS  Google Scholar 

  • Calhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, Staufenbiel M, Sommer B, Jucker M (1998) Neuron loss in APP transgenic mice. Nature 395(6704):755–756. doi:10.1038/27351

    Article  PubMed  CAS  Google Scholar 

  • Carroll JC, Rosario ER, Chang L, Stanczyk FZ, Oddo S, LaFerla FM, Pike CJ (2007) Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci 27(48):13357–13365. doi:10.1523/JNEUROSCI.2718-07.2007

    Article  PubMed  CAS  Google Scholar 

  • Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T, Drobecq H, Clark A, Bonici B, Delacourte A, Benavides J, Schmitz C, Tremp G, Bayer TA, Benoit P, Pradier L (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300

    Article  PubMed  CAS  Google Scholar 

  • Chan-Palay V, Asan E (1989) Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression. J Comp Neurol 287(3):357–372. doi:10.1002/cne.902870307

    Article  PubMed  CAS  Google Scholar 

  • Doya K (2008) Modulators of decision making. Nat Neurosci 11(4):410–416. doi:10.1038/nn2077

    Article  PubMed  CAS  Google Scholar 

  • Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383(6602):710–713. doi:10.1038/383710a0

    Article  PubMed  CAS  Google Scholar 

  • Duyckaerts C, Potier MC, Delatour B (2008) Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol 115(1):5–38. doi:10.1007/s00401-007-0312-8

    Article  PubMed  Google Scholar 

  • Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, 3rd edn. Elsevier/Academic Press, Amsterdam, Boston

    Google Scholar 

  • German DC, Manaye KF, White CL 3rd, Woodward DJ, McIntire DD, Smith WK, Kalaria RN, Mann DM (1992) Disease-specific patterns of locus coeruleus cell loss. Ann Neurol 32(5):667–676. doi:10.1002/ana.410320510

    Article  PubMed  CAS  Google Scholar 

  • Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28(3):327–335. doi:10.1016/j.neurobiolaging.2006.02.007

    Article  PubMed  CAS  Google Scholar 

  • Gundersen HJ, Jensen EB, Kieu K, Nielsen J (1999) The efficiency of systematic sampling in stereology—reconsidered. J Microsc 193(Pt 3):199–211

    Article  PubMed  CAS  Google Scholar 

  • Holcomb I, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzaen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O’Campo K, Hardy J, Prada C, Eckman C, Younkin S, Hsiao K, Duff K (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100

    Article  PubMed  CAS  Google Scholar 

  • Lee GD, Aruna JH, Barrett PM, Lei DL, Ingram DK, Mouton PR (2005) Stereological analysis of microvascular parameters in a double transgenic model of Alzheimer’s disease. Brain Res Bull 65(4):317–322. doi:10.1016/j.brainresbull.2004.11.024

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Yoo MJ, Savonenko A, Stirling W, Price DL, Borchelt DR, Mamounas L, Lyons WE, Blue ME, Lee MK (2008) Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer’s disease. J Neurosci 28(51):13805–13814. doi:10.1523/JNEUROSCI.4218-08.2008

    Article  PubMed  CAS  Google Scholar 

  • Long JM, Kalehua AN, Muth NJ, Calhoun ME, Jucker M, Hengemihle JM, Ingram DK, Mouton PR (1998) Stereological analysis of astrocyte and microglia in aging mouse hippocampus. Neurobiol Aging 19(5):497–503. doi:10.1016/S0197-4580(98)00088-8

    Article  PubMed  CAS  Google Scholar 

  • Manaye KF, McIntire DD, Mann DM, German DC (1995) Locus coeruleus cell loss in the aging human brain: a non-random process. J Comp Neurol 358(1):79–87. doi:10.1002/cne.903580105

    Article  PubMed  CAS  Google Scholar 

  • Manaye KF, Wang PC, O’Neil JN, Huang SY, Xu T, Lei DL, Tizabi Y, Ottinger MA, Ingram DK, Mouton PR (2007) Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry. Age (Dordr) 29(2–3):87–96. doi:10.1007/s11357-007-9035-y

    Article  CAS  Google Scholar 

  • Manaye KF, Allard JS, Kalifa S, Drew AC, Xu G, Ingram DK, Cabo RD, Mouton PR (2010) 17alpha-estradiol attenuates neuron lossin ovariectomized Dtg AbetaPP/PS1 mice. J Alzheimers Dis. doi:10.3233/JAD-2010-100993

  • Mastrangelo MA, Bowers WJ (2008) Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer’s disease-related pathologies in male triple-transgenic mice. BMC Neurosci 9:81. doi:10.1186/1471-2202-9-81

    Article  PubMed  Google Scholar 

  • Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430(7000):631–639. doi:10.1038/nature02621nature02621

    Article  PubMed  CAS  Google Scholar 

  • Mega MS, Cummings JL, Fiorello T, Gornbein J (1996) The spectrum of behavioral changes in Alzheimer’s disease. Neurology 46(1):130–135

    Article  PubMed  CAS  Google Scholar 

  • Mouton PR (2002) Principles and practices of unbiased stereology: an introduction for bioscientists. The Johns Hopkins University Press, Baltimore

    Google Scholar 

  • Mouton PR, Pakkenberg B, Gundersen HJ, Price DL (1994) Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals. J Chem Neuroanat 7(3):185–190. doi:10.1016/0891-0618(94)90028-0

    Article  PubMed  CAS  Google Scholar 

  • Mouton PR, Chachich ME, Quigley C, Spangler E, Ingram DK (2009) Caloric restriction attenuates cortical amyloidosis in a double transgenic mouse model of Alzheimer’s disease. Neurosci Lett 464:184–187

    Article  PubMed  CAS  Google Scholar 

  • Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140

    Article  PubMed  CAS  Google Scholar 

  • O’Neil JN, Mouton PR, Tizabi Y, Ottinger MA, Lei DL, Ingram DK, Manaye KF (2007) Catecholaminergic neuronal loss in locus coeruleus of aged female dtg APP/PS1 mice. J Chem Neuroanat 34(3–4):102–107. doi:10.1016/j.jchemneu.2007.05.008

    Article  PubMed  Google Scholar 

  • Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003a) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 24(8):1063–1070

    Article  PubMed  CAS  Google Scholar 

  • Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003b) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409–421

    Article  PubMed  CAS  Google Scholar 

  • Oh KJ, Perez SE, Lagalwar S, Vana L, Binder L, Mufson EJ (2010) Staging of Alzheimer’s pathology in triple transgenic mice: a light and electron microscopic analysis. Int J Alzheimers Dis 2010. doi:10.4061/2010/780102

  • Ohm TG, Busch C, Bohl J (1997) Unbiased estimation of neuronal numbers in the human nucleus coeruleus during aging. Neurobiol Aging 18(4):393–399

    Article  PubMed  CAS  Google Scholar 

  • Overk CR, Kelley CM, Mufson EJ (2009) Brainstem Alzheimer’s-like pathology in the triple transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 35(3):415–425. doi:10.1016/j.nbd.2009.06.004

    Article  PubMed  CAS  Google Scholar 

  • Price JL, Davis PB, Morris JC, White DL (1991) The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging 12(4):295–312

    Article  PubMed  CAS  Google Scholar 

  • Ridley RM, Timothy CJ, Maclean CJ, Baker HF (1995) Conditional learning and memory impairments following neurotoxic lesion of the CA1 field of the hippocampus. Neuroscience 67(2):263–275. doi:10.1016/0306-4522(95)00063-O

    Article  PubMed  CAS  Google Scholar 

  • Rohn TT, Vyas V, Hernandez-Estrada T, Nichol KE, Christie LA, Head E (2008) Lack of pathology in a triple transgenic mouse model of Alzheimer’s disease after overexpression of the anti-apoptotic protein Bcl-2. J Neurosci 28(12):3051–3059. doi:10.1523/JNEUROSCI.5620-07.2008

    Article  PubMed  CAS  Google Scholar 

  • Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309(5733):476–481. doi:10.1126/science.1113694

    Article  PubMed  CAS  Google Scholar 

  • Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10(3):211–223. doi:10.1038/nrn2573

    Article  PubMed  CAS  Google Scholar 

  • Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F, Markowska AL, Borchelt DR (2005) Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 18(3):602–617. doi:10.1016/j.nbd.2004.10.022

    Article  PubMed  CAS  Google Scholar 

  • Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99(2):195–231

    Article  PubMed  CAS  Google Scholar 

  • van Dooren T, Dewachter I, Borghgraef P, van Leuven F (2005) Transgenic mouse models for APP processing and Alzheimer’s disease: early and late defects. Subcell Biochem 38:45–63

    Article  PubMed  Google Scholar 

  • Weinshenker D (2008) Functional consequences of locus coeruleus degeneration in Alzheimer’s disease. Curr Alzheimer Res 5(3):342–345

    Article  PubMed  CAS  Google Scholar 

  • West MJ (1993) Regionally specific loss of neurons in the aging human hippocampus. Neurobiol Aging 14(4):287–293

    Article  PubMed  CAS  Google Scholar 

  • West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231(4):482–497. doi:10.1002/ar.1092310411

    Article  PubMed  CAS  Google Scholar 

  • West MJ, Kawas CH, Martin LJ, Troncoso JC (2000) The CA1 region of the human hippocampus is a hot spot in Alzheimer’s disease. Ann N Y Acad Sci 908:255–259

    Article  PubMed  CAS  Google Scholar 

  • West MJ, Bach G, Soderman A, Jensen JL (2009) Synaptic contact number and size in stratum radiatum CA1 of APP/PS1DeltaE9 transgenic mice. Neurobiol Aging 30(11):1756–1776. doi:10.1016/j.neurobiolaging.2008.01.009

    Article  PubMed  CAS  Google Scholar 

  • Yu AJ, Dayan P (2005) Uncertainty, neuromodulation, and attention. Neuron 46(4):681–692. doi:10.1016/j.neuron.2005.04.026

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from the US Public Health Service NINDS/NIH, SNRP 2U54NS039409-10 (KFM), R01 AG0245478 (RST), R44MH076541-04 (PRM), and GU Pilot Grant (KFM).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kebreten F. Manaye.

About this article

Cite this article

Manaye, K.F., Mouton, P.R., Xu, G. et al. Age-related loss of noradrenergic neurons in the brains of triple transgenic mice. AGE 35, 139–147 (2013). https://doi.org/10.1007/s11357-011-9343-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-011-9343-0

Keywords

Navigation