Full-length review
The role of neuronal growth factors in neurodegenerative disorders of the human brain

https://doi.org/10.1016/S0165-0173(98)00004-6Get rights and content

Abstract

Recent evidence suggests that neurotrophic factors that promote the survival or differentiation of developing neurons may also protect mature neurons from neuronal atrophy in the degenerating human brain. Furthermore, it has been proposed that the pathogenesis of human neurodegenerative disorders may be due to an alteration in neurotrophic factor and/or trk receptor levels. The use of neurotrophic factors as therapeutic agents is a novel approach aimed at restoring and maintaining neuronal function in the central nervous system (CNS). Research is currently being undertaken to determine potential mechanisms to deliver neurotrophic factors to selectively vulnerable regions of the CNS. However, while there is widespread interest in the use of neurotrophic factors to prevent and/or reduce the neuronal cell loss and atrophy observed in neurodegenerative disorders, little research has been performed examining the expression and functional role of these factors in the normal and diseased human brain. This review will discuss recent studies and examine the role members of the nerve growth factor family (NGF, BDNF and NT-3) and trk receptors as well as additional growth factors (GDNF, TGF-α and IGF-I) may play in neurodegenerative disorders of the human brain.

Introduction

Neuronal cell death as a result of neurotrophic factor deprivation is a physiological cell death mechanism which is commonly observed during neuronal development 14, 201, 236, 359. Many neurons within the vertebrate nervous system require the presence of neurotrophic factors such as nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) for survival 14, 359. It has been proposed that growing axons compete for limited amounts of neurotrophic factors which are produced by the target tissues. Neurons which fail to obtain a sufficient quantity of the necessary neurotrophic factor die by a process of programmed cell death [14]. This process is thought to regulate the number of neurons and neuronal connections within the developing central nervous system (CNS). The neurotrophic factor family has been proposed to play a role in the neuroprotection of specific neuronal populations by suppressing the expression of `suicide genes' which, when activated are involved in the induction of apoptotic processes 14, 236, 359. This proposal suggests that when the level of neurotrophic factor expression fall below that required to suppress the activation of `suicide genes', transcriptional processes may result in the induction of apoptotic mechanisms.

While the mechanisms involved in the neuronal loss that occurs following a reduction in neurotrophic support have been determined in the developing nervous system, researchers are still unclear as to what implications deficits in trophic support have in the adult CNS. While it has been observed that several neuronal populations within the adult CNS require the presence of neurotrophic factors to maintain neuronal function and phenotype 82, 88, 424, it is unclear as to the degree to which mature neurons remain dependent upon target-derived support. If mature neurons are still dependent upon the presence of neurotrophic factors for survival and function then the loss of transcriptional suppression of the `suicide programme' due to a reduction in neurotrophic factor expression may result in the neuronal atrophy seen in normal aging or the neuronal loss observed in neurodegenerative disorders such as Alzheimer's disease (AD) [236]. Indeed, it has been proposed 20, 189that AD pathology may primarily be due to a deficit in neurotrophic factor protein and/or tyrosine kinase (trk) receptor expression.

Research is currently being undertaken in order to determine whether members of the neurotrophic factor family have potential therapeutic roles in preventing and/or reducing the neuronal cell loss and atrophy that occurs in neurodegenerative disorders such as AD, Parkinson's disease (PD), Huntington's disease (HD) or amyotrophic lateral sclerosis (ALS). The use of neurotrophic factors as therapeutic agents is a novel approach aimed at restoring and maintaining neuronal function in the CNS. Neurotrophic factors have the potential to protect diseased and injured neurons from dying, induce neuronal sprouting and to increase neuronal metabolism and function. Research is currently being undertaken to determine potential mechanisms to deliver neurotrophic factors to selectively vulnerable regions of the CNS. However, while the expression of neurotrophic factors and their high-affinity trk receptors has been fully characterised in the rodent CNS, little research has been performed examining the expression and functional role of these factors in the normal and diseased human brain. In this review, we will discuss the regional distribution and functional role of individual neurotrophic factors and trk receptors in the CNS. We will also examine the role neurotrophic factors and trk receptors may play in the pathogenesis of neurodegenerative disorders, both in vitro and in vivo, with particular emphasis on the therapeutic use of these factors to prevent and/or reduce selective neuronal loss in the diseased human brain. The reader is referred to previous reviews discussing the pathophysiological aspects of human neurodegenerative disorders 50, 61, 64, 65, 126, 148, 176, 180, 183, 185, 214, 230, 231, 275, 373, 406. Throughout this review, the term neurotrophin/neurotrophic factor will be loosely used to cover members of the NGF family (NGF, BDNF and NT-3) and additional growth factors including insulin-like growth factor (IGF-I), glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-α (TGF-α).

Section snippets

Mechanisms of selective neuronal cell death in neurodegenerative disorders

Two mechanisms of neuronal cell death have been identified within the CNS—necrosis and apoptosis. Apoptosis is defined as a process of active cell death, characterised by cell and nuclear shrinkage, chromatin condensation and membrane blebbing. In contrast, necrosis has been characterised by cellular swelling and lysis resulting in a cytokine-mediated inflammatory response. While necrosis results in the appearance of random DNA fragmentation, apoptosis is associated with the cleavage of DNA

The function of NGF

NGF was first discovered by Levi-Montalcini in 1951 [287]. High concentrations of NGF were observed in the mouse submaxillary glands resulting in the cloning of the NGF gene in several species 150, 305, 401, 466. Since its discovery, NGF has become one of the best characterised members of the neurotrophin family. NGF consists of three subunits, α, β and γ which interact to form a 7S complex of approximately 27 kDa in weight. The 7S complex contains two identical 118 amino acid β chains which

Identification and cloning

A second target-derived neurotrophic factor, BDNF, has been detected within the CNS 305, 337. BDNF is a basic dimeric 28-kDa protein of non-covalently linked 14-kDa subunits structurally related to NGF 382, 383, 475. Recombinant human BDNF (rhBDNF) was recently cloned and the protein sequence of mature human BDNF was observed to be identical to the porcine and rat sequences indicating conservation across species [366].

Regional distribution of BDNF within the CNS

BDNF mRNA and protein levels have been detected in the hippocampus, amygdala,

Identification and cloning of NT-3

Utilising information obtained on the structural homology of the neurotrophic factor family, researchers cloned a gene encoding NT-3 135, 209, 304. The predicted size of the NT-3 polypeptide is 199 amino acids and the mature rat NT-3 peptide displays a 57% amino acid identity with rat NGF and a 58% amino acid identity with rat BDNF. However, despite this structural homology, NT-3 has distinct biological activity and a different spatiotemporal characteristic from both NGF and BDNF.

Regional distribution of NT-3 within the CNS

In contrast to

Identification of the structure and regional distribution

The observation that the rat glial cell line, B49 released a factor which exhibited relative specificity for dopaminergic neurons in dissociated cultures of the rat embryonic midbrain lead to the identification of a new member of the neurotrophic family 134, 291, 293. This potential neurotrophic factor was purified, cloned and identified as GDNF 291, 292. GDNF is a glycosylated, disulfide-bonded homodimer that is distantly related to members of the TGF-β superfamily. The molecular weight of the

The structure of TGF-α and the EGF/TGF-α receptor

TGF-α, a member of the epidermal growth factor (EGF) family of mitogenic polypeptides 66, 103, has also been observed to provide trophic support and promote the differentiation of CNS neurons in vitro. TGF-α was initially identified in the medium of retrovirus-transformed rodent cells 170, 306and extensive sequence homology was found among TGF polypeptides from different species and cell types. The mature 50 amino acid form of TGF-α is derived from a 160 amino acid transmembrane precursor by

Identification and regional distribution

Current research is also focused on determining the potential role members of the IGF family may have in preventing neuronal injury or reducing neuronal degeneration. The presence of IGFs and their receptors in the CNS has raised the possibility that the IGFs may play a role in brain development, neuronal and glial phenotypic differentiation, glial cell growth and neuronal outgrowth 37, 289. The IGFs are mitogenic polypeptides with insulin-like metabolic activity [352]and two IGF molecules,

The identification of binding sites for NGF—the dual receptor binding system

The receptor signaling system of the neurotrophic factor family is unique in that it consists of two transmembrane receptor proteins, the trk family of receptors and the low-affinity p75 receptor. Each of the neurotrophic factors are capable of interacting with the low-affinity p75 receptor and a specific trk receptor 35, 235, 305, 317. The first major study into the identification and description of NGF receptors focused on binding sites observed in chick sensory ganglia cells 100, 437. Two

Conclusion

In conclusion, the research to date indicates a potential role for neurotrophic factors in the treatment of neurodegenerative disorders. However, it still remains unclear as to whether alterations in neurotrophic factor or trk receptor expression are primary or secondary to the neuropathological changes associated with each disorder. Indeed, while it has not been determined whether alterations in neurotrophic factor or trk receptor expression precede the development of the disease process, it

Acknowledgements

This research was supported by the New Zealand Neurological Foundation, the Health Research Council of New Zealand, the New Zealand Lotteries Health Board and the Auckland University Research Committee. Bronwen Connor holds a Health Research Council of New Zealand Postgraduate Scholarship.

References (500)

  • E. Arenas et al.

    GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo

    Neuron

    (1995)
  • M.A. Bach et al.

    Insulin-like growth factor I mRNA levels are developmentally regulated in specific regions of the rat brain

    Mol. Brain Res.

    (1991)
  • M. Ballarin et al.

    Hippocampal damage and kainic acid injection induce a rapid increase in BDNF and NGF mRNA in the rat brain

    Exp. Neurol.

    (1991)
  • M. Barbacid et al.

    The trk family of tyrosine protein kinase receptors

    Biochim. Biophys. Acta

    (1991)
  • D.G. Baskin et al.

    Insulin and insulin-like growth factors in the CNS

    Trends Neurosci.

    (1988)
  • C. Behl et al.

    Amyloid β peptide induces necrosis rather than apoptosis

    Brain Res.

    (1994)
  • E.J. Beilharz et al.

    Differential expression of insulin-like growth factor binding proteins (IGFBP) 4 and 5 mRNA in the rat brain after transient hypoxic–ischemic injury

    Mol. Brain Res.

    (1993)
  • A. Bjorklund et al.

    Studies of neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson's disease

    Neurobiol. Dis.

    (1997)
  • D. Blum et al.

    p53 and Bax activation in 6-hydroxydopamine-induced apoptosis in PC12 cells

    Brain Res.

    (1997)
  • N.J. Bohannon et al.

    Localization of binding sites for insulin-like growth factor-I (IGF-I) in the rat brain by quantitative autoradiography

    Brain Res.

    (1988)
  • L.H. Boise et al.

    bcl-x, a bcl-2 related gene that functions as a dominant regulator of apoptotic cell death

    Cell

    (1993)
  • C. Bondy et al.

    Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: comparison with insulin-like growth factors I and II

    Neuroscience

    (1992)
  • W.J. Bowers et al.

    Gene therapeutic strategies for neuroprotection: implications for Parkinson's disease

    Exp. Neurol.

    (1997)
  • R. Brachmann et al.

    Transmembrane TGFα precursors activate EGF/TGFα receptors

    Cell

    (1989)
  • A.L. Brown et al.

    Nucleotide sequence and expression of a cDNA clone encoding a fetal rat binding protein for insulin-like growth factor

    J. Biol. Chem.

    (1989)
  • G. Bruce et al.

    Production and characterisation of biologically active recombinant human nerve growth factor

    Neurobiol. Aging

    (1989)
  • S.K. Burgess et al.

    Characterization of a neuronal subtype of a insulin-like growth factor I receptor

    J. Biol. Chem.

    (1987)
  • I. Burgos et al.

    NGF-mediated synaptic sprouting in the cerebral cortex of lesioned primate brain

    Brain Res.

    (1995)
  • M.A. Burke et al.

    Loss of developing cholinergic basal forebrain neurons following excitotoxic lesions of the hippocampus: rescue by neurotrophins

    Exp. Neurol.

    (1994)
  • L.L. Butcher et al.

    Neurotrophic agents may exacerbate the pathological cascade of Alzheimer's disease

    Neurobiol. Aging

    (1989)
  • M.J. Carson et al.

    Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice

    Neuron

    (1993)
  • M.V. Chao et al.

    p75 and Trk: a two-receptor system

    Trends Neurosci.

    (1995)
  • V. Charles et al.

    Atrophy of cholinergic basal forebrain neurons following excitotoxic cortical lesions is reversed by intravenous administration of an NGF conjugate

    Brain Res.

    (1996)
  • K.S. Chen et al.

    Role of neurotrophic factors in Alzheimer's disease

    Neurobiol. Aging

    (1989)
  • S.-Y. Chen et al.

    Neuropathology of synthetic beta-amyloid peptide analogs in vivo

    Brain Res.

    (1996)
  • D. Collerton

    Cholinergic function and intellectual decline in Alzheimer's disease

    Neuroscience

    (1986)
  • B. Connor et al.

    Trk receptor alterations in Alzheimer's disease

    Mol. Brain Res.

    (1996)
  • B. Connor et al.

    Insulin-like growth factor (IGF-1) immunoreactivity in the Alzheimer's disease temporal cortex and hippocampus

    Mol. Brain Res.

    (1997)
  • B. Connor et al.

    Brain-derived neurotrophic factor is reduced in Alzheimer's disease

    Mol. Brain Res.

    (1997)
  • J.D. Cooper et al.

    Reduced transport of [I] nerve growth factor by cholinergic neurons and down-regulated TrkA expression in the medial septum of aged rats

    Neuroscience

    (1994)
  • J.D. Cooper et al.

    Delayed death of septal cholinergic neurons after excitotoxic ablation of hippocampal neurons during early postnatal development in the rat

    Exp. Neurol.

    (1996)
  • N. Cristina et al.

    GDNF: existence of a second transcript in the brain

    Mol. Brain Res.

    (1995)
  • C. Crowley et al.

    Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons

    Cell

    (1994)
  • R. Curtis et al.

    Differential role of the low affinity neurotrophin receptor (p75) in retrograde axonal transport of the neurotrophins

    Neuron

    (1995)
  • J.B. Davis

    Oxidative mechanisms in beta-amyloid cytotoxicity

    Neurodegeneration

    (1996)
  • G. Dechant et al.

    Neurotrophin receptors

    Prog. Neurobiol.

    (1994)
  • A. Acheson et al.

    Non target-derived roles of the neurotrophins

    Phil. Trans. R. Soc. London Ser. B: Biol. Sci.

    (1996)
  • A. Acheson et al.

    A BDNF autocrine loop in adult sensory neurons prevents cell death

    Nature

    (1995)
  • F. Aguado et al.

    Immunohistochemical localization of insulin-like growth factor I in the hypothalamo–hypophyseal system of the adult rat

    Neuroendocrinology

    (1992)
  • M.E. Alexianu et al.

    Apoptotic cell death of a hybrid motoneuron cell line induced by immunoglobulins from patients with amyotrophic lateral sclerosis

    J. Neurochem.

    (1994)
  • Cited by (0)

    View full text