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Erik Edström
erik.edstrom@ki.se
Curriculum Vitae
Thesis Project and Abstracts
Full Publication List
Curriculum Vitae
Research Student at the Department of Neuroscience since 1997.
Teacher of Anatomy for Medical Students since 1997.
Member of the Society for Neuroscience since 1998.
PhD Student at the Department of Neuroscience since 2000
Teacher of Anatomy for Physiotherapy Students since 2000.
MD at Karolinska Institutet 2001.
Thesis
Project and Abstracts
Thesis Project Research
Plan
Aim
Background
Animal model
Methods
Project progress
Neuromuscular junction
Target
innervation and target dependence
Cytokine signaling
Endocrinology
Global approach
Abstracts
Thesis Project
Research Plan
Studies on ageing-related changes in the neuromuscular system with special
reference to neuron-target interactions.
Aim
The main aim of this project is to investigate changes in the neuromuscular
system of relevance for motor dysfunctions in senescence.
Background
Aging motoneurons show a distinct pattern of phenotypic changes, while loss of
motoneurons is small (~15% at 30 month of age) despite frequent (~75%) and overt
signs of behavioral motor deficits (Johnson,
1995). Several studies have reported on a loss of large myelinated axons in
aged peripheral nerves but these results are questioned (see Knox,
1989, and references therein) and, moreover, do not evidence that motor
axons, in fact, are gone. The reason for this is that aged motor axons frequently
show extensive signs of axon dystrophy, atrophy and aberrations in their myelination
(Knox,
1989, and references therein) and may, therefore, not have been included in
quantitative estimates. Thus, even in the very old individual with profound behavioral
impairment, the vast majority of motoneurons are still present but apparently
not connected to an intact set of target muscle cells. Consistent with the distribution
of behavioral motor deficits, aging-related axon lesions are more prevalent in
ventral roots and peripheral nerves of the lumbar than the cervical spinal cord
(Van
Steenis, 1971; Burek,
1976). Furthermore, the distal part of a nerve is more severely affected than
the proximal part (Sharma,
1980; Krinke,
1983), suggesting that this is progressing in a distal-to-proximal direction.
A successive dropout of motoneurons would fit with the pattern of changes seen
in aging skeletal muscle. Particularly, in the initial phase of muscle denervation,
motoneurons still connected to the muscle may try to compensate through collateral
re-innervation (Larsson, 1982; Edström,
1987; Larsson,
1995), a process where terminal Schwann cells may play a key role (reviewed
by Son,
1996). However, if senile muscle atrophy would be caused purely by a neurogenic
mechanism, it is difficult to explain why aging motoneurons are not lost, why
they have a preserved cholinergic phenotype and display no signs of cell body
atrophy. Both CGRP and growth-associated protein 43 (GAP43) are markedly upregulated
in aged motoneurons, a regulatory pattern typical of growth and regeneration (Johnson,
1995). It has also been shown that aged motoneurons appear to have a preserved
capacity to regenerate target muscle fibers following experimental axon damage
(Kanda,
1991; Kawabuchi,
1995). Thus, evidence indicates that the process underlying senile muscle
atrophy is more complex than just a drop-out of parent motoneurons. In this context
it should also be considered that muscle fibers can be replenished from satellite
cells (Campion,
1984), but this capacity is low in adulthood and seems to decay even further
in senescence (Schultz,
1982; Emery, 1993; Ferrari,
1998). Thus, number of muscle fibers may decrease during aging due to a restrained
regenerative capacity of the muscle tissue itself.
In addition to the upregulation of CGRP and GAP43, aged motoneurons
disclose a highly specific pattern of NFL (nerve growth factor family of
ligands) and GFL (glial derived growth factor ligands) receptor regulation.
This pattern shares some similarity but also distinct differences from
that expressed by adult motoneurons disconnected from the target.
Animal
model
We use aged rodents with impairments of cognitive, sensory and motor functions
as revealed by standardized behavioral tests. So far, we have mainly utilized
rats (see Appendix), but
mice are becoming increasingly important in our work.
Methods
1. Behavioral analysis, including tests of motor, sensory and cognitive
functions.
2. Gene expression analysis: macro and micro gene-array screening;
Northern blot; RT-PCR. Protein analysis with Western blot. Cellular analysis:
immunohistochemistry and in situ hybridization.
3. Experimental paradigms; including environmental, surgical and chemical
manipulations.
Project
progress
· The first paper Erik Edström co-authored, addressed the issue
of the lowered expression-level of trk receptors in aged motoneurons (c.f.
Johnson et al., 1996, 1999).
Reciprocal changes in the expression of neurotrophin
mRNAs in target tissues and peripheral nerves of aged rats, Yu Ming, Esbjörn
Bergman, Erik Edström and Brun Ulfhake, Neuroscience Lettrers, 273:
187-190, 1999.
In aged rats, skeletal muscles show a downregulation
of all four members of the nerve growth factor family of neurotrophins,
and the degree of decrease correlated with the extent of behavioral sensorimotor
impairment among the individuals. Thus, animals with minor symptoms show
a preserved expression of BDNF and only NT4 of the NFLs discloses a robust
downregulation (>40%) also in behaviorally fairly intact aged animals.
The expression level of muscle NT4 increases postnatally and several lines
of evidence indicate that NT4 is positively regulated by neuromuscular
junction (NMJ) impulse activity in adulthood (Funakoshi,
1993; Funakoshi,
1995; Griesbeck,
1995). Some evidence point at the intriguing possibility that muscle-derived
NT4 may have a strictly local signal-enhancing effect on the NMJ (Wang,
1998), and that retrograde transport of NT4 is a p75NTR dependent process
taking place in lesioned but not intact motor axons (Koliatsos, 1994; Curtis,
1995; Rydén, 1995). This is consistent with the marked upregulation,
from very low levels, of p75NTR in adult motoneurons subjected to axon
lesion (Ernfors, 1989; Koliatsos, 1991). It seems quite plausible that
the regulation of muscle NT4 in senescence reflects the decreased motor
activity typical of aged rats. A decreased motor activity may not necessarily
reflect a decreased innervation of the muscle. The concomitant lowering
of NGF, NT3 and BDNF in the target would not be expected if neuromuscular
aging was exclusively due to a drop-out of motoneurons. Rather it suggests
a possible incapacitation of the target to maintain adult expression levels
of NFLs.
Aged motoneurons show a robust downregulation of trkC, evident
also in individuals with only minor behavioral deficits (Johnson, 1999). The
downregulation probably reflects lowered levels of NT3 in the target, since
other potential sources of the trkC ligand NT3 such as PSN in DRGs, the spinal
cord or its motor nuclei, express NT3 at unaltered levels in senescence (Johnson,
1999; Ming,
1999b). In contrast to adult motoneurons disconnected from their target,
trkB expression is also decreased in aged motoneurons. This downregulation is
less marked in animals with mild symptoms of impairment, while animals with
severe symptoms show a more robust decrease of trkB (Johnson,
1999). The changed pattern of trkB expression in aged motoneurons closely
mirrors the changes seen for BDNF in the target muscles. Furthermore, the levels
of trkB ligands in DRGs and spinal cord appear largely unchanged with advancing
age, arguing against that altered access to alternative sources of ligands is
mechanistic in the downregulation of trkB (Johnson,
1999; Ming,
1999b). Thus it seems reasonable to infer that trkB is downregulated in
aged motoneurons due to a decreased access to target-derived ligands.
Taken together, the pattern of regulation of neurotrophins and
trk receptor transcripts in senescence suggest that spinal motoneurons
compete for a decreasing amount of target-derived trk ligands. The loss
of muscle fibers and the atrophy of the remaining fibers, will combined
impose a reduced target size where the remaining muscle fibers express
neurotrophins at decreased level.
· A second paper co-authored by Erik Edström addressed the
issue of GDNF – GFR/ret signaling in aging motoneurons.
Evidence for increased GDNF signaling in aged sensory
and motor neurons, Yu Ming, Esbjörn Bergman, Erik Edström and
Brun Ulfhake
NeuroReport 10:1529-1535, 1999.
GDNF is one of the most potent neurotrophic factors found so
far for motoneurons. In adulthood it is present in glia cells and in peripheral
target tissues, and the preferred receptor compliment is expressed by motoneurons.
In aged rats there is an upregulation in spinal motoneurons of both the binding
protein GFRa-1 and the signal transducing RET components of the GDNF receptor
(Bergman,
1999c). The target muscles show a marked upregulation of GDNF (Ming,
1999a). A more modest upregulation of GDNF is also evident in the peripheral
nerves but not in the spinal cord of aged rats. Combined this set of data imply
an increased GDNF signaling between, in particular, the target muscles and the
motoneurons. This may serve as a compensatory mechanism in the context of decreased
NFL-trk signaling in aging motoneurons, promoting axon regeneration (Naveilhan,
1997; Trupp, 1997), sprouting and muscle fiber re-innervation (Nguyen, 1998);
and may be mechanistic in the protection of cell body size and cholinergic phenotype.
In support of the latter, is Sagot and coworkers (1996) report that in pmn/pmn
mice, suffering a lethal mutation causing severe muscle dystrophy and progressive
caudal-cranial motoneuron degeneration, exogenous GDNF could prevent cell body
atrophy and protect the cholinergic phenotype of the motoneurons but not impede
the progressive damage of the axons. It has also been shown that GDNF has inhibitory
effects on the generation of radical oxygen species (Irie, 1999) and, thus, may
work in orchestra with p75NTR to protect aging motoneurons from oxidative
stress.
A crucial point, yet unresolved due to the method used in the
study by Ming et al. (1999),
is if the cellular source of GDNF is the muscle fibers or the terminal Schwann
cells located in the muscle tissue (Ming,
1999a; Suzuki, 1999). If the increased levels of GDNF derive from terminal
Schwann cells, it could serve as a compensatory mechanism sustaining motoneurons
when target muscle fibers become incapacitated. However, if the upregulation takes
place in muscle fibers, we need to decode a highly specific and complex regulation
of different neurotrophic factors in the target muscle cells during aging.
Erik Edström is currently addressing
several issues related to the studies described above:
· The cellular source of GDNF in aging muscles is examined employing
in situ techniques.
Neuromuscular
junction
· Studies of changes in the expression of different molecules involved
in the operation and maintenance of the neuromuscular junction (NMJ) with
advancing age. For example, motoneurons produce and release several factors
that regulate muscle acetylcholin receptor expression (AChR). One such
factor, neuregulin (NRG, ARIA) (Falls, 1993; Lemke, 1996) increases AChR
transcription through activation of muscle expressed erbB receptors (Carraway
III, 1994). NRG is expressed by motoneurons during development and in adulthood,
but becomes downregulated in senescence (Edström et al., in preparation).
Loeb and Fishbach (1997) showed that, in particular, BDNF and NT3 can upregulate
NRG in motoneurons. Interestingly, the isoform of NRG most likely to bind
to the basal lamina of the NMJ was only upregulated by BDNF. Although direct
evidence is lacking, the downregulation of NRG in motoneurons may represent
yet another consequence of a decreased NFL signaling in senescence.
Target
innervation and target dependence
· A set of experiments is designed to investigate the function of
the aging motor axon, including capacity to sustain target innervation
and to re-innervate the target. The importance of the target will be further
examined by artificial reduction of target size (without interference with
the innervation), overload and disuse of the muscles. Changes of the capacity
to replenish muscle cells from satellite cells in senescence will also
be examined.
· Neurotrophic signaling will be manipulated using blocking
(antisense; neutralizing antibodies) and artificial delivery (through viral
vector) strategies
Cytokine
signaling
· Another important line in Erik Edström’s research will be
to expand to cytokine families such as inflammatory cytokines/interleukins,
neuropoietic cytokines and growth factors. A number of these cytokines
are of obvious interest since they also have neurotrophic function (e.g.
CNTF and LIF).
Endocrinology
· The relevance of certain hormones is obvious. In particular, the
GH-IGF axis is examined and preliminary data indicate that IGF is upregulated
in aging rodent muscle tissue (E. Edström, in preparation). Due to
the emergence of adreno-, andro- and menopause in senescence (for review
see Lamberts et al., 1997; Weeks and Lewin, 1995; Toran-Allerand and co-workers,
1994, 1996) examination and manipulation of sex steroids will be carried
out.
Global
approach
· In parallel, to the specific issues addressed in the studies outlined
above, macro- and micro gene expression arrays are being employed to “profile”
expression changes in the target muscle tissue, peripheral nerve and spinal
cord motor nuclei during aging.
Abstracts
Changed expression of neurotrophins
and neurotrophin receptors in peripheral sensory pathways during aging.
Bergman, E., Fundin, B.T., Ming, Y., Edström, E. and B.
Ulfhake.
Society for neuroscience, 1999. Abstract.
Evidence for decreased neurotrophin-trk
signaling in aged motoneurons.
Edström, E., Johnson, H., Ming, Y., Bergman, E. and B.
Ulfhake.
Society for neuroscience, 1999. Abstract.
Evidence for increased GDNF-GFR?-1/RET signaling
in aged sensory and motor neurons.
Ming, Y., Bergman, E., Edström, E., Kullberg, S. and B.
Ulfhake.
Society for neuroscience, 1999. Abstract.
Full
Publication List
Evidence
for increased GDNF signaling in aged sensory and motor neurons.
Ming Y, Bergman E, Edstrom E, Ulfhake B
Neuroreport 1999 May 14;10(7):1529-35. PubMed
Reciprocal
changes in the expression of neurotrophin mRNAs in target tissues and peripheral
nerves of aged rats.
Ming Y, Bergman E, Edstrom E, Ulfhake B
Neurosci Lett. 1999 Oct 8;273(3):187-90. PubMed
Regulation
of neurotrophin signaling in aging sensory and motoneurons. Dissipation of
target support?
Ulfhake B, Bergman E, Edstrom E, Fundin BT, Johnson H, Kullberg S,
Ming Y.
Mol Neurobiol 2000 Jun;21(3):109-35. PubMed
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