Skip to main content
SpringerLink
Log in

In Vivo Imaging of Axonal Transport in Aging and Alzheimer’s Disease

  • Chapter
  • First Online:
Cytoskeleton of the Nervous System

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 3))

  • 1025 Accesses

Abstract

In neurons, the process of axonal transport helps maintain health and homeostasis for normal neuronal functions. Protein products, synthesized in the cell body and organelles such as mitochondria, are transported via molecular “motors” to the synapse for incorporation into membranes or cytoskeletal architecture, release into the synaptic cleft, or use in synaptic functioning. Retrograde transport occurs when substances, such as trophic factors, are taken up from the synaptic cleft via endocytosis and are transported back to the cell body to modulate further protein synthesis. Although retrograde transport is an important neuronal process, this chapter will focus on imaging of anterograde axonal transport and the effects of aging and neurodegeneration. Because axonal transport mechanisms become even more critical to maintain neuronal function in neuronal populations with long axonal projections, perturbations of axonal transport may contribute to the selective vulnerability of cortical projection neurons in neurodegenerative processes such as Alzheimer’s disease (AD). With the increasing longevity of the world’s population, aging and age-related diseases are becoming a major healthcare issue. Research in the areas of brain aging is critical, not only to maintaining life, but also to maintaining quality of life and sustaining a fully functional, independent, elderly population. Aging is also known to be a major risk factor for AD. According to pathological observations, cortical projection neurons are particularly vulnerable to AD pathophysiology (Hof et al., 1990). In such neurons, the process of axonal transport is particularly crucial to sustaining neuronal homeostasis and functions. Certain systems can be challenging to investigate non-invasively due to the relative inaccessibility of some brain regions and the technical challenges inherent in studying dynamic, sub-cellular processes. Therefore, the methodology to study axonal transport in living brains has been limited. This chapter will present on-going efforts to investigate this critical process using recently developed in vivo imaging techniques.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

ATP:

Adenosine triphosphate

Aβ:

Amyloid-beta

FDG-PET:

(F-18) Flurodeoxyglucose and positron emission tomography

GSK-3:

Glycogen synthase kinase 3

MEMRI:

Manganese-enhanced magnetic resonance imaging

VOI:

Volume of interest

References

  • Adalbert R, Nogradi A, Babetto E, Janeckova L, Walker SA, Kerschensteiner M, Misgeld T, Coleman MP (2009) Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies. Brain 132(Pt 2):402–416

    PubMed  Google Scholar 

  • Albers MW, Tabert MH, Devanand DP (2006) Olfactory dysfunction as a predictor of neurodegenerative disease. Curr Neurol Neurosci Rep 6(5):379–386

    Article  PubMed  Google Scholar 

  • Aschner M, Vrana KE, Zheng W (1999) Manganese uptake and distribution in the central nervous system (CNS). Neurotoxicology 20(2–3):173–180

    CAS  PubMed  Google Scholar 

  • Attems J, Jellinger KA (2006) Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol 25(6):265–271

    CAS  PubMed  Google Scholar 

  • Barrios FA, Gonzalez L, Favila R, Alonso ME, Salgado PM, Diaz R, Fernandez-Ruiz J (2007) Olfaction and neurodegeneration in HD. Neuroreport 18(1):73–76

    Article  PubMed  Google Scholar 

  • Brady ST (2000) Neurofilaments run sprints not marathons. Nat Cell Biol 2(3):E43–E45

    Article  CAS  PubMed  Google Scholar 

  • Brenneman KA, Wong BA, Buccellato MA, Costa ER, Gross EA, Dorman DC (2000) Direct olfactory transport of inhaled manganese ((54)MnCl(2)) to the rat. Toxicol Appl Pharmacol 169(3):238–248

    Article  CAS  PubMed  Google Scholar 

  • Brunetti M, Miscena A, Salviati A, Gaiti A (1987) Effect of aging on the rate of axonal transport of choline-phosphoglycerides. Neurochem Res 12(1):61–65

    Article  CAS  PubMed  Google Scholar 

  • Caccamo A, Oddo S, Tran LX, LaFerla FM (2007) Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol 170(5):1669–1675

    Article  CAS  PubMed  Google Scholar 

  • Cash AD, Aliev G, Siedlak SL, Nunomura A, Fujioka H, Zhu X, Raina AK, Vinters HV, Tabaton M, Johnson AB, Paula-Barbosa M, Avila J, Jones PK, Castellani RJ, Smith MA, Perry G (2003) Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am J Pathol 162(5):1623–1627

    Article  CAS  PubMed  Google Scholar 

  • Cross DJ, Flexman JA, Anzai Y, Maravilla KR, Minoshima S (2008) Age-related decrease in axonal transport measured by MR imaging in vivo. Neuroimage 39(3):915–926

    Article  PubMed  Google Scholar 

  • Cross DJ, Flexman JA, Anzai Y, Sasaki T, Treuting PM, Maravilla KR, Minoshima S (2007) In vivo manganese MR imaging of calcium influx in spontaneous rat pituitary adenoma. AJNR Am J Neuroradiol 28(10):1865–1871

    Article  CAS  PubMed  Google Scholar 

  • Dai J, Buijs RM, Kamphorst W, Swaab DF (2002) Impaired axonal transport of cortical neurons in Alzheimer’s disease is associated with neuropathological changes. Brain Res 948(1–2):138–144

    Article  CAS  PubMed  Google Scholar 

  • Engel T, Goni-Oliver P, Lucas JJ, Avila J, Hernandez F (2006) Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J Neurochem 99(6):1445–1455. Epub 2006 Oct 24

    Article  CAS  PubMed  Google Scholar 

  • Enwere E, Shingo T, Gregg C, Fujikawa H, Ohta S, Weiss S (2004) Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci 24(38):8354–8365

    Article  CAS  PubMed  Google Scholar 

  • Fiala J, Feinberg M, Peters A, Barbas H (2007) Mitochondrial degeneration in dystrophic neurites of senile plaques may lead to extracellular deposition of fine filaments. Brain Struct Funct 212(2):195–207

    Article  PubMed  Google Scholar 

  • Fibiger HC, Pudritz RE, McGeer PL, McGeer EG (1972) Axonal transport in nigro-striatal and nigro-thalamic neurons: effects of medial forebrain bundle lesions and 6-hydroxydopamine. J Neurochem 19(7):1697–1708

    Article  CAS  PubMed  Google Scholar 

  • Firbank MJ, Blamire AM, Krishnan MS, Teodorczuk A, English P, Gholkar A, Harrison RM, O’Brien JT (2007) Diffusion tensor imaging in dementia with Lewy bodies and Alzheimer’s disease. Psychiatry Res 155:135–145

    Article  PubMed  Google Scholar 

  • Frolkis VV, Tanin SA, Gorban YN (1997) Age-related changes in axonal transport. Exp Gerontol 32(4–5):441–450

    Article  CAS  PubMed  Google Scholar 

  • Gallez B, Baudelet C, Geurts M (1998) Regional distribution of manganese found in the brain after injection of a single dose of manganese-based contrast agents. Magn Reson Imaging 16(10):1211–1215

    Article  CAS  PubMed  Google Scholar 

  • Gavin CE, Gunter KK, Gunter TE (1990) Manganese and calcium efflux kinetics in brain mitochondria. relevance to manganese toxicity. Biochem J 266(2):329–334

    CAS  PubMed  Google Scholar 

  • Gianutsos G, Morrow GR, Morris JB (1997) Accumulation of manganese in rat brain following intranasal administration. Fundam Appl Toxicol 37(2):102–105

    Article  CAS  PubMed  Google Scholar 

  • Ho DT, Schlosser P, Caplow T (2002) Determination of longitudinal dispersion coefficient and net advection in the tidal hudson river with a large-scale, high resolution SF6 tracer release experiment. Environ Sci Technol 36(15):3234–3241

    Article  CAS  PubMed  Google Scholar 

  • Hof PR, Cox K, Morrison JH (1990) Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer’s disease: I. Superior frontal and inferior temporal cortex. J Comp Neurol 301(1):44–54

    Article  CAS  PubMed  Google Scholar 

  • Jacob JM, O’Donoghue DL (1995) Direct measurement of fast axonal transport rates in corticospinal axons of the adult rat. Neurosci Lett 197(1):17–20

    Article  CAS  PubMed  Google Scholar 

  • Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS (2001) Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 414(6864):643–648

    Article  CAS  PubMed  Google Scholar 

  • Kasa P, Papp H, Kovacs I, Forgon M, Penke B, Yamaguchi H (2000) Human amyloid-beta1-42 applied in vivo inhibits the fast axonal transport of proteins in the sciatic nerve of rat. Neurosci Lett 278(1–2):117–119

    Article  CAS  PubMed  Google Scholar 

  • Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B (2004) Imaging brain amyloid in Alzheimer’s disease with pittsburgh compound-B. Ann Neurol 55(3):306–319

    Article  CAS  PubMed  Google Scholar 

  • Kreutzberg GW (1969) Neuronal dynamics and axonal flow. IV. Blockage of intra-axonal enzyme transport by colchicine. Proc Natl Acad Sci USA 62(3):722–728

    Article  CAS  PubMed  Google Scholar 

  • Leergaard TB, Bjaalie JG, Devor A, Wald LL, Dale AM (2003) In vivo tracing of major rat brain pathways using manganese-enhanced magnetic resonance imaging and three-dimensional digital atlasing. Neuroimage 20(3):1591–1600

    Article  PubMed  Google Scholar 

  • Levin BE (1977) Axonal transport of [3H]fucosyl glycoproteins in noradrenergic neurons in the rat brain. Brain Res 130(3):421–432

    Article  CAS  PubMed  Google Scholar 

  • Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293(5534):1487–1491

    Article  CAS  PubMed  Google Scholar 

  • Luzzi S, Snowden JS, Neary D, Coccia M, Provinciali L, Lambon Ralph MA (2007) Distinct patterns of olfactory impairment in Alzheimer’s disease, semantic dementia, frontotemporal dementia, and corticobasal degeneration. Neuropsychologia 45(8):1823–1831

    Article  PubMed  Google Scholar 

  • Masuoka DT, Jonsson G, Finch CE (1979) Aging and unusual catecholamine-containing structures in the mouse brain. Brain Res 169(2):335–341

    Article  CAS  PubMed  Google Scholar 

  • McNeill TH, Koek LL, Haycock JW (1984) The nigrostriatal system and aging. Peptides 5(Suppl 1):263–268

    Article  CAS  PubMed  Google Scholar 

  • McQuarrie IG, Brady ST, Lasek RJ (1989) Retardation in the slow axonal transport of cytoskeletal elements during maturation and aging. Neurobiol Aging 10(4):359–365

    Article  CAS  PubMed  Google Scholar 

  • Minoshima S, Cross D (2008) In vivo imaging of axonal transport using MRI: aging and Alzheimer’s disease. Eur J Nucl Med Mol Imaging, 35(Suppl 1):S89–92

    Article  PubMed  Google Scholar 

  • Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE (1997) Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 42(1):85–94

    Article  CAS  PubMed  Google Scholar 

  • Morfini G, Pigino G, Beffert U, Busciglio J, Brady ST (2002) Fast axonal transport misregulation and Alzheimer’s disease. Neuromolecular Med 2(2):89–99

    Article  CAS  PubMed  Google Scholar 

  • Mudher A, Shepherd D, Newman TA, Mildren P, Jukes JP, Squire A, Mears A, Drummond JA, Berg S, MacKay D, Asuni AA, Bhat R, Lovestone S (2004) GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry 9(5):522–530

    Article  CAS  PubMed  Google Scholar 

  • Narita K, Kawasaki F, Kita H (1990) Mn and Mg influxes through Ca channels of motor nerve terminals are prevented by verapamil in frogs. Brain Res 510(2):289–295

    Article  CAS  PubMed  Google Scholar 

  • NIH (2007) news briefs: new Alzheimer’s clinical trials to be undertaken by NIA nationawide consortium. Am J Alzheimers Dis Other Demen 21:460–462. doi:10.1177/1533317506297573

    Article  Google Scholar 

  • Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102(19):6990–6995. Epub 2005 May 2

    Article  CAS  PubMed  Google Scholar 

  • Ochs S (1972) Fast transport of materials in mammalian nerve fibers. Science 176(32):252–260

    Article  CAS  PubMed  Google Scholar 

  • Ochs S (1973) Effect of maturation and aging on the rate of fast axoplasmic transport in mammalian nerve. Prog Brain Res 40(0):349–362

    Article  CAS  PubMed  Google Scholar 

  • Ochs S (1975) A unitary concept of axoplasmic transport based on the transport filament hypothesis. In: Bradley W et al. (eds) Recent advances in myology, vol 360. Excerpta Medica, Amsterdam, pp 189–194

    Google Scholar 

  • Parhad IM, Scott JN, Cellars LA, Bains JS, Krekoski CA, Clark AW (1995) Axonal atrophy in aging is associated with a decline in neurofilament gene expression. J Neurosci Res 41(3):355–366

    Article  CAS  PubMed  Google Scholar 

  • Pautler RG, Koretsky AP (2002) Tracing odor-induced activation in the olfactory bulbs of mice using manganese-enhanced magnetic resonance imaging. Neuroimage 16(2):441–448

    Article  PubMed  Google Scholar 

  • Pautler RG, Silva AC, Koretsky AP (1998) In vivo neuronal tract tracing using manganese-enhanced magnetic resonance imaging. Magn Reson Med 40(5):740–748

    Article  CAS  PubMed  Google Scholar 

  • Phiel CJ, Wilson CA, Lee VM, Klein PS (2003) GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 423(6938):435–439

    Article  CAS  PubMed  Google Scholar 

  • Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J (2003) Alzheimer’s presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci 23(11):4499–4508

    CAS  PubMed  Google Scholar 

  • Praprotnik D, Smith MA, Richey PL, Vinters HV, Perry G (1996) Filament heterogeneity within the dystrophic neurites of senile plaques suggests blockage of fast axonal transport in Alzheimer’s disease. Acta Neuropathol (Berl) 91(3):226–235

    Article  CAS  Google Scholar 

  • Rashid DJ, Bononi J, Tripet BP, Hodges RS, Pierce DW (2005) Monomeric and dimeric states exhibited by the kinesin-related motor protein KIF1A. J Pept Res 65(6):538–549

    Article  CAS  PubMed  Google Scholar 

  • Rockenstein E, Torrance M, Adame A, Mante M, Bar-on P, Rose JB, Crews L, Masliah E (2007) Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci 27(8):1981–1991

    Article  CAS  PubMed  Google Scholar 

  • Saleem KS, Pauls JM, Augath M, Trinath T, Prause BA, Hashikawa T, Logothetis NK (2002) Magnetic resonance imaging of neuronal connections in the macaque monkey. Neuron 34(5):685–700

    Article  CAS  PubMed  Google Scholar 

  • Shea TB (2000) Microtubule motors, phosphorylation and axonal transport of neurofilaments. J Neurocytol 29(11/12):873–887

    Article  CAS  PubMed  Google Scholar 

  • Sloot WN, Gramsbergen JB (1994) Axonal transport of manganese and its relevance to selective neurotoxicity in the rat basal ganglia. Brain Res 657(1/2):124–132

    Article  CAS  PubMed  Google Scholar 

  • Smith KD, Kallhoff V, Zheng H, Pautler RG (2007) In vivo axonal transport rates decrease in a mouse model of Alzheimer’s disease. Neuroimage 35(4):1401–1408. Epub 2007 Feb 12

    Article  PubMed  Google Scholar 

  • Stokin GB, Goldstein LS (2006a) Axonal transport and Alzheimer’s disease. Annu Rev Biochem 75:607–627

    Article  CAS  PubMed  Google Scholar 

  • Stokin GB, Goldstein LS (2006b) Linking molecular motors to Alzheimer’s disease. J Physiol Paris 99(2/3):193–200

    Article  CAS  PubMed  Google Scholar 

  • Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307(5713):1282–1288

    Article  CAS  PubMed  Google Scholar 

  • Stromska DP, Ochs S (1982) Axoplasmic transport in aged rats. Exp Neurol 77(1):215–224

    Article  CAS  PubMed  Google Scholar 

  • Takashima A (2006) GSK-3 is essential in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis 9(3 Suppl):309–317

    CAS  PubMed  Google Scholar 

  • Takeda A, Kodama Y, Ishiwatari S, Okada S (1998) Manganese transport in the neural circuit of rat CNS. Brain Res Bull 45(2):149–152

    Article  CAS  PubMed  Google Scholar 

  • Tesseur I, Van DJ, Bruynseels K, Bronfman F, Sciot R, Van LA, Van LF (2000) Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am J Pathol 157(5):1495–1510

    Article  CAS  PubMed  Google Scholar 

  • Tjalve H, Henriksson J (1999) Uptake of metals in the brain via olfactory pathways. Neurotoxicology 20(2–3):181–195

    CAS  PubMed  Google Scholar 

  • Tjalve H, Henriksson J, Tallkvist J, Larsson BS, Lindquist NG (1996) Uptake of manganese and cadmium from the nasal mucosa into the central nervous system via olfactory pathways in rats. Pharmacol Toxicol 79(6):347–356

    Article  CAS  PubMed  Google Scholar 

  • Tomishige M, Klopfenstein DR, Vale RD (2002) Conversion of Unc104/KIF1A kinesin into a processive motor after dimerization. Science 297(5590):2263–2267

    Article  CAS  PubMed  Google Scholar 

  • Uchida A, Tashiro T, Komiya Y, Yorifuji H, Kishimoto T, Hisanaga S (2004) Morphological and biochemical changes of neurofilaments in aged rat sciatic nerve axons. J Neurochem 88(3):735–745

    Article  CAS  PubMed  Google Scholar 

  • Vahlsing HL, Hirschl RB, Feringa ER (1981) Axoplasmic flow of tritiated proline in the corticospinal tract of the rat. Cell Tissue Res 214(2):279–287

    Article  CAS  PubMed  Google Scholar 

  • Van der Linden A, Verhoye M, Van Meir V, Tindemans I, Eens M, Absil P, Balthazart J (2002) In vivo manganese-enhanced magnetic resonance imaging reveals connections and functional properties of the songbird vocal control system. Neuroscience 112(2):467–474

    Article  PubMed  Google Scholar 

  • Verdu E, Ceballos D, Vilches JJ, Navarro X (2000) Influence of aging on peripheral nerve function and regeneration. J Peripher Nerv Syst 5(4):191–208

    Article  CAS  PubMed  Google Scholar 

  • Watanabe T, Michaelis T, Frahm J (2001) Mapping of retinal projections in the living rat using high-resolution 3D gradient-echo MRI with Mn2+-induced contrast. Magn Reson Med 46(3):424–429

    Article  CAS  PubMed  Google Scholar 

  • Weiss P, Hiscoe HB (1948) Experiments on the mechanism of nerve growth. J Exp Zool 107(3):315–395

    Article  CAS  PubMed  Google Scholar 

  • Zhang B, Higuchi M, Yoshiyama Y, Ishihara T, Forman MS, Martinez D, Joyce S, Trojanowski JQ, Lee VM (2004) Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy. J Neurosci 24(19):4657–4667

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiology, University of Washington, Seattle, WA, 98195, USA

    Donna J. Cross & Satoshi Minoshima

  2. Department of Bioengineering, University of Washington, Seattle, WA, USA

    Satoshi Minoshima

Authors
  1. Donna J. Cross
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satoshi Minoshima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Donna J. Cross .

Editor information

Editors and Affiliations

  1. Psychiatric Research, Nathan S. Kline Institute for, 140 Old Orangeburg Road, Orangeburg, 10962, New York, USA

    Ralph A. Nixon

  2. Psychiatric Research, Nathan S. Kline Institute for, 140 Old Orangeburg Road, Orangeburg, 10962, New York, USA

    Aidong Yuan

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Cross, D.J., Minoshima, S. (2011). In Vivo Imaging of Axonal Transport in Aging and Alzheimer’s Disease. In: Nixon, R., Yuan, A. (eds) Cytoskeleton of the Nervous System. Advances in Neurobiology, vol 3. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6787-9_23

Download citation

Publish with us

Policies and ethics

Search

Navigation