Elsevier

Progress in Neurobiology

Volume 63, Issue 1, 1 January 2001, Pages 71-124
Progress in Neurobiology

Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease

https://doi.org/10.1016/S0301-0082(00)00014-9Get rights and content

Abstract

Brain-derived neurotrophic factor (BDNF) is a small dimeric protein, structurally related to nerve growth factor, which is abundantly and widely expressed in the adult mammalian brain. BDNF has been found to promote survival of all major neuronal types affected in Alzheimer’s disease and Parkinson’s disease, like hippocampal and neocortical neurons, cholinergic septal and basal forebrain neurons, and nigral dopaminergic neurons. In this article, we summarize recent work on the molecular and cellular biology of BDNF, including current ideas about its intracellular trafficking, regulated synthesis and release, and actions at the synaptic level, which have considerably expanded our conception of BDNF actions in the central nervous system. But our primary aim is to review the literature regarding BDNF distribution in the human brain, and the modifications of BDNF expression which occur in the brain of individuals with Alzheimer’s disease and Parkinson’s disease. Our knowledge concerning BDNF actions on the neuronal populations affected in these pathological states is also reviewed, with an aim at understanding its pathogenic and pathophysiological relevance.

Introduction

The discovery of neurotrophins (NTs) followed an interesting series of experiments demonstrating that the survival of peripheral nervous system neurons during development depends on target availability and size. An excess number of sensory and sympathetic neurons is produced during early development, and then, programmed cell death occurs until the number of surviving neurons matches the size of the target (reviewed by Oppenheim, 1991, Hamburger, 1993). Strikingly, implanted tumoral tissue can serve as target for host embryonic peripheral nervous system neurons, and promotes survival and differentiation of sensory and sympathetic neurons (Bueker, 1948, Hamburger and Levi-Montalcini, 1949; Levi-Montalcini and Hamburger, 1951). Further work showed that the effect of tumors depended on the production of a diffusible agent, a protein which was finally named nerve growth factor (NGF) (Levi-Montalcini and Hamburger, 1953; reviewed by Levi-Montalcini, 1987, Hamburger, 1993). NGF could be isolated from mouse salivary glands (where it is highly concentrated), allowing the obtention of antibodies, with the demonstration that endogenous NGF is necessary for the development of some peripheral nervous system neurons in mammals (Cohen, 1960, Levi-Montalcini and Booker, 1960, Johnson et al., 1980). This discovery was followed by the demonstrations that target tissues of sympathetic and sensory neurons produce NGF (Davies et al., 1987), that peripheral neurons express NGF receptors (Sutter et al., 1979), and that NGF is retrogradely transported to their cell bodies (Dumas et al., 1979), findings that ultimately led to the concept of target-derived neurotrophic support (reviewed by Levi-Montalcini, 1987, Thoenen et al., 1987, Purves et al., 1988, Oppenheim, 1991). Cloning of mouse and human NGF genes was finally accomplished in 1983 (Scott et al., 1983, Ullrich et al., 1983). The NGF low-affinity and high-affinity receptors, whose existence was initially demonstrated on the basis of physiological and ligand binding studies (Levi-Montalcini, 1987), have also been characterized at the genetic and molecular levels (Barbacid, 1994a, Barbacid, 1994b, Ultsch et al., 1999). Recent studies on genetically-modified mice lacking NGF, or its high-affinity receptor Tropomiosin receptor kinase A (TrkA), support that NGF is necessary for survival of peripheral sensory and sympathetic neurons (Crowley et al., 1994, Smeyne et al., 1994).

The earlier exciting discoveries on NGF physiology stimulated further work aimed at isolating other neurotrophic molecules. Brain-derived neurotrophic factor (BDNF) was purified from pig brain, thanks to its survival-promoting action on a subpopulation of dorsal root ganglion neurons (Barde et al., 1982). The amino acid sequence of mature BDNF has a strong homology with that of NGF (Leibrock et al., 1989, Rosenthal et al., 1991), a fact that encouraged the search of other sequence-related molecules, nowadays known as neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) (Ernfors et al., 1990a, Hohn et al., 1990, Jones and Reichardt, 1990, Kaisho et al., 1990, Rosenthal et al., 1990, Maisonpierre et al., 1990a, Maisonpierre et al., 1991, Berkemeier et al., 1991, Hallböök et al., 1991, Ip et al., 1992). The search for other sequence-related molecules still continues, and has recently led to the identification of new NTs in the bony fish (Götz et al., 1994, Nilsson et al., 1998, Lai et al., 1998) and lamprey (Hallböök et al., 1998). Thus far, only four NTs have been found in humans. All NTs bind the low-affinity receptor for NGF, at present known as p75 neurotrophin receptor (p75NTR). In addition, other high-affinity NT receptors, structurally related to TrkA, have been identified. TrkB binds BDNF and NT-4/5, whereas NT-3 binds to TrkC, and with reduced efficacy, to TrkB (reviewed by Barbacid, 1994a, Barbacid, 1994b, Chao, 1994, Dechant et al., 1994).

As is the case for NGF, BDNF is necessary for survival of some peripheral sensory neurons, notably those in the vestibular ganglia and nodose-petrosum ganglia. Interestingly, part of the trophic effects of BDNF in the peripheral nervous system seem to depend on autocrine loops and paracrine interactions between adjacent neurons, since sensory neurons can express both BDNF and its high affinity receptor TrkB. These studies have been repeatedly reviewed before (Barde, 1989; Korsching, 1993; Davies, 1994, Klein, 1994; Snider, 1994; Lewin and Barde, 1996, Barde, 1999). In addition, BDNF is abundantly expressed in the central nervous system, specially in the hippocampal formation, cerebral cortex, and amygdaloid complex (Hofer et al., 1990, Ernfors et al., 1990a, Ernfors et al., 1990b, Wetmore et al., 1990, Phillips et al., 1990), and its expression increases until reaching a maximal level after birth (Maisonpierre et al., 1990b, Friedman et al., 1991a, Friedman et al., 1991b, Schecterson and Bothwell, 1992). Then, the expression of BDNF seems not to decline with age (Lapchak et al., 1993b, Narisawa-Saito and Nawa, 1996, Katoh-Semba et al., 1997, Katoh-Semba et al., 1998). These facts suggest essential roles for BDNF in the adult central nervous system.

The idea, that neuronal death in degenerative disorders can result from the lack of an endogenous trophic molecule, was in the mind of the research community at the beginning of the 1980s (Appel, 1981, Hefti, 1983). Following the knowledge acquired on NGF actions in the peripheral nervous system, the target-derived neurotrophic support concept was extended to populations of adult central nervous system neurons, in particular the cholinergic septal and basal forebrain neurons which degenerate in Alzheimer’s disease (reviewed by Thoenen et al., 1987, Hefti et al., 1989 and more recently by Hefti, 1999). Septal and basal forebrain cholinergic neurons express both low- and high-affinity receptors for NGF, project to the hippocampal formation and cerebral cortex (the main central nervous system sites for NGF synthesis), and retrogradely transport NGF from these target structures to their cell bodies (Hefti, 1999). Destruction of the hippocampal formation or cerebral cortex leads to atrophy of septal and cholinergic neurons (Sofroniew et al., 1993, Burke et al., 1994, Skup et al., 1994), and similar effects can be obtained by administering immunotoxins directed against p75NTR (Heckers et al., 1994, Wenk et al., 1994), mutating the TrkA gene (Smeyne et al., 1994), the gene encoding for p75NTR (Vanderzee et al., 1996), or the NGF gene itself (Chen et al., 1997). Finally, NGF administration prevents cholinergic neuron atrophy caused by lesions of the septohippocampal and basal forebrain–cortical systems (Hefti, 1999). The compiled evidence led to the suggestion that NGF administration might produce some benefit to individuals with Alzheimer’s disease (Hefti, 1999).

BDNF is more highly expressed and widely distributed than NGF in the central nervous system, and has survival promoting actions on a variety of central nervous system neurons including hippocampal and cortical neurons (Ghosh et al., 1994, Lowenstein and Arsenault, 1996, Lindholm et al., 1996), cholinergic neurons (Alderson et al., 1990, Knüsel et al., 1991), and nigral dopaminergic neurons (Hyman et al., 1991, Knüsel et al., 1991). Of course, these facts raised keen interest in BDNF as a potential therapeutic agent for Parkinson’s disease and Alzheimer’s disease, among other neurodegenerative disorders and non-degenerative pathologies. This interest has been intensified by reports demonstrating a reduced expression of BDNF in the brain of individuals with Alzheimer’s disease (Phillips et al., 1991, Murray et al., 1994, Narisawa-Saito et al., 1996) and Parkinson’s disease (Mogi et al., 1999, Parain et al., 1999).

This article reviews the distribution of BDNF in the human control brain, and the reports revealing changes in BDNF expression in Alzheimer’s disease and Parkinson’s disease, with an aim to understand how an altered expression of BDNF can be involved in the pathogeny and pathophysiology of these diseases. There is a section that summarizes the knowledge acquired on BDNF molecular and cellular biology during the last decade, in order to render the review understandable for readers from other fields. Recent ideas about BDNF distribution within neurons, and on BDNF actions at the synaptic level are presented, to gain insight into the functional interactions between populations of central nervous system neurons which express BDNF and TrkB. Then, the distribution of BDNF in the human control brain, and the changes observed in Alzheimer’s disease and Parkinson’s disease are described. In addition, the actions of BDNF on the neuronal populations affected by both diseases are reviewed more extensively, to offer a broad panorama on the mechanisms through which an altered BDNF expression can be involved in the pathogeny and pathophysiology of Alzheimer’s and Parkinson’s diseases.

Section snippets

BDNF is a member of the neurotrophin family

As outlined in the Section 1, BDNF is a member of the NT family, the other human members are NGF, NT-3 and NT-4/5. All four genes coding for NTs have been found in fish, amphibians, reptiles, and mammals (Isackson et al., 1991a, Götz and Schartl, 1994, Hallböök et al., 1998). The sequence of the mature form of human BDNF (hBDNF) is identical to that of porcine, rat and mouse BDNF (Hofer et al., 1990, Rosenthal et al., 1991), shows 90% identity as compared to teleost fish BDNF (Götz et al., 1992

Distribution of BDNF in the adult human brain

In this section the anatomical distribution of BDNF in the adult human control brain is reviewed. The description is mainly based on our own immunocytochemical studies (Murer et al., 1999a), and fragmentary data provided by several other research groups on BDNF protein or mRNA distribution in discrete brain regions. In addition, we compare the distribution of BDNF protein between human, monkey and rat brain. Information about BDNF mRNA distribution (proceeding mainly from studies performed in

Brain-derived neurotrophic factor in Alzheimer’s disease and Parkinson’s disease

The expression of BDNF in the human central nervous system is altered by several pathological processes, including neurodegenerative diseases (see below), epilepsy (Nawa et al., 1995, Mathern et al., 1997, Takahashi et al., 1999), and hypoxia-ischemia, and hypoglycemia (Lindvall et al., 1992, Merlio et al., 1993, Korhonen et al., 1998). The following section examines evidence demonstrating changes in BDNF expression in Alzheimer’s disease and Parkinson’s disease (see also Table 1). When

Conclusion

Our knowledge about the anatomical distribution and physiology of BDNF has grown enormously during the last decade, and suggests that BDNF is not only important for the normal development of the peripheral and central nervous system, but that also has relevant actions in the adult central nervous system, and might be involved in the pathogeny and pathophysiology of central nervous system diseases, notably Alzheimer’s disease and Parkinson’s disease. Among the advances in the field attained

Note added in proof

Holsinger et al. (2000) further confirmed levels of BDNF mRNA are reduced in the brain (parietal cortex) of individuals with Alzheimer's disease. Ferrer et al. (2000) reported that BDNF protein is not decreased in frontotemporal dementia. This fact suggests that the decrease in BDNF expression which occurs in Alzheimer's disease is not a phenomenon common to all kinds of dementia. Murray et al. (2000) provided additional evidence demonstrating an increased expression of BDNF mRNA in dentate

Acknowledgements

The authors would like to thank to INSERM and CNRS (France), Universidad de Buenos Aires, CONICET, Fundación Roemmers and Fundación Antorchas (Argentina) for financial support, and F. Boisière, N. Sertour, J. Villares, S. Hunot, K. Parain, P. Michel, M. Ruberg, E. Hirsch, Y. Agid, and B. Faucheux (INSERM U289, Paris, France), and F. Kasanetz and K. Tseng (Universidad de Buenos Aires, Buenos Aires, Argentina), for their participation in the experiments on BDNF.

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