Elsevier

Neuroscience

Volume 88, Issue 4, February 1999, Pages 1015-1032
Neuroscience

An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer's disease

https://doi.org/10.1016/S0306-4522(98)00219-XGet rights and content

Abstract

Brain-derived neurotrophic factor is a member of the family of neuronal differentiation and survival-promoting molecules called neurotrophins. Neuronal populations known to show responsiveness to the action of brain-derived neurotrophic factor include the cholinergic forebrain, mesencephalic dopaminergic, cortical, hippocampal and striatal neurons. This fact has aroused considerable interest in the possible contribution of an abnormal brain-derived neurotrophic factor function to the aetiology and physiopathology of different neurodegenerative disorders, such as Alzheimer's disease. This report describes the cellular and regional distribution of brain-derived neurotrophic factor in post mortem control human brain and in limited regions of the brain in patients with Alzheimer's disease, as was revealed by immunohistochemistry. Brain-derived neurotrophic factor is widely expressed in the control human brain, both by neurons and glia. In neurons, brain-derived neurotrophic factor was localized in the cell body, dendrites and axons. Among the structures showing the most intense immunohistochemical labeling were the hippocampus, claustrum, amygdala, bed nucleus of the stria terminalis, septum and the nucleus of the solitary tract. In the striatum, immunoreactivity was more intense in striosomes than in the matrix. Many labeled neurons were found in the substantia nigra pars compacta. The large putatively cholinergic neurons in the basal forebrain showed no immunoreactivity. The general pattern of labeling was similar in individuals with Alzheimer's disease.

Brain-derived neurotrophic factor-immunoreactive material was found in senile plaques, and some immunoreactive cortical pyramidal neurons showed neurofibrilary tangles, suggesting that brain-derived neurotrophic factor may be involved in the process of neuronal degeneration and/or compensatory mechanisms which occur in this illness.

Section snippets

Brain samples and tissue preparation

Experiments were performed on post mortem brain tissue from four subjects with no known history of neurological or psychiatric illness and three patients with clinical and neuropathological diagnosis of Alzheimer's disease. Neuropathological diagnosis of Alzheimer's disease was based on the high density of silver-impregnated senile plaques[10]observed in the temporal and frontal cortices and the low density of acetylcholinesterase histochemical staining in the ventral striatum.[51]Clinical and

Specificity of the antiserum

As reported for rat brain, BDNF immunoreactivity is widely expressed throughout the human CNS (Table 2, Table 3). Preabsorption of anti-BDNF antibodies with rhBDNF abolished staining in sections of the hippocampus (Fig. 1C) and claustrum (not shown). Omission of the primary antibodies resulted in an absence of labeling of CNS structures with the exception of cerebellar granule cells, which showed a slight non-specific immunoreactivity (Fig. 6B).

The antibody was further characterized by

Discussion

To our knowledge, this is the first comprehensive immunohistochemical study on the distribution of BDNF in the human brain. Our main findings can be summarized as follows: (i) as reported for other mammals, BDNF is widely expressed in the normal adult human brain; (ii) BDNF immunoreactivity was observed in the cytoplasm of neuronal cell bodies and proximal dendrites, axons and nerve terminals; (iii) BDNF immunoreactivity was also present in glial cells and processes; (iv) BDNF-immunoreactive

Conclusion

This study demonstrates a widespread expression of BDNF in the adult human brain, thus suggesting that it has important functions beyond the period of development and early postnatal growth. In addition to extending previous animal findings to humans, we have provided new details on the localization of BDNF, such as the presence of BDNF-containing axons in the neuropile of most cholinergic nuclei, preferential labeling of striosomes in the striatum and glial immunostaining. A detailed knowledge

Unlinked references

43, 58, 84

Acknowledgements

This study was supported by grants from INSERM and CNRS (France), and Fundación Antorchas of Argentina (GM). We are indebted to Nick Barton for revising the manuscript.

References (88)

  • J Jimenez-Castellanos et al.

    Subdivisions of the dopamine-containing A8–A9–A10 complex identified by their differential mesostriatal innervation of striosomes and extrastriosomal matrix

    Neuroscience

    (1987)
  • K.R Jones et al.

    Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development

    Cell

    (1994)
  • Y Kawamoto et al.

    Immunohistochemical localization of brain-derived neurotrophic factor in adult rat brain

    Neuroscience

    (1996)
  • D.C Lo

    Neurotrophic factors and synaptic plasticity

    Neuron

    (1995)
  • P.C Maisonpierre et al.

    NT-3, BDNF and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression

    Neuron

    (1990)
  • N.Q McDonald et al.

    A structural superfamily of growth factors containing a knot motif

    Cell

    (1993)
  • K.D Murray et al.

    Differential regulation of brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase messenger RNA expression in Alzheimer's disease

    Neuroscience

    (1994)
  • S.L Patterson et al.

    Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knock-out mice

    Neuron

    (1996)
  • H.S Phillips et al.

    BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease

    Neuron

    (1991)
  • H Sauer et al.

    Brain-derived neurotrophic factor and neurotrophin-4/5 modify neurotransmitter-related gene expression in the 6-hydroxydopamine-lesioned rat striatum

    Neuroscience

    (1995)
  • B.H Turner et al.

    MPTP produces a pattern of nigrostriatal degeneration which coincides with the mosaic organization of the caudate nucleus

    Brain Res.

    (1988)
  • Q Yan et al.

    Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system

    Neuroscience

    (1997)
  • P Zhang et al.

    Distribution of manganese-dependent superoxide dismutase in the human brain

    Neuroscience

    (1994)
  • S Alcántara et al.

    TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death

    J. Neurosci.

    (1997)
  • C.A Altar et al.

    Efficacy of brain-derived neurotrophic factor and neurotrophin-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions

    J. Neurochem.

    (1994)
  • Y.-A Barde et al.

    Purification of a new neurotrophic factor from mammalian brain

    Eur. molec. Biol. Org. J.

    (1982)
  • K.D Beck et al.

    Induction of non-catalytic trkB neurotrophin receptors during axonal sprouting in the adult hippocampus

    J. Neurosci.

    (1993)
  • Benisty S., Boissière F., Faucheux B., Agid Y. and Hirsch E. (1998) TrkB mRNA expression in the normal human brain and...
  • E Birecree et al.

    Immunoreactive epidermal growth factor receptors in neuritic plaques from patients with Alzheimer's disease

    J. Neuropath. exp. Neurol.

    (1988)
  • D Bodian

    A new method for staining nerve fibers and nerve endings in mounted paraffin sections

    Anat. Rec.

    (1936)
  • F Boissière et al.

    Nuclear translocation of NF-kB in cholinergic neurons of patients with Alzheimer's disease

    NeuroReport

    (1997)
  • S Ceccatelli et al.

    Expanded distribution of mRNA for nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the rat brain after colchicine treatment

    Proc. natn. Acad. Sci. U.S.A.

    (1991)
  • M.V Chao

    The p75 neurotrophin receptor

    J. Neurobiol.

    (1994)
  • E.-Y Chen et al.

    Trk and p75 neurotrophin receptor systems in the developing human brain

    J. comp. Neurol.

    (1996)
  • J.M Conner et al.

    Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport

    J. Neurosci.

    (1997)
  • J.C Conover et al.

    Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4

    Nature

    (1995)
  • D.W Dickson et al.

    Ubiquitin immunoelectron microscopy of dystrophic neurites in cerebellar senile plaques of Alzheimer's disease

    Acta neuropath., Berlin

    (1990)
  • M.M Dugich-Djordjevic et al.

    Immunohistochemical visualization of brain-derived neurotrophic factor in the rat brain

    Eur. J. Neurosci.

    (1995)
  • F Eblen et al.

    Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey

    J. Neurosci.

    (1995)
  • P Eikelenboom et al.

    Cellular and substrate adhesion molecules (integrins) and their ligands in cerebral amyloid deposits in Alzheimer's disease

    Virchows Arch.

    (1994)
  • S Elkabes et al.

    Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function

    J. Neurosci.

    (1996)
  • P Ernfors et al.

    Mice lacking brain-derived neurotrophic factor develop with sensory deficits

    Nature

    (1994)
  • A Figurov et al.

    Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus

    Nature

    (1996)
  • W.J Friedman et al.

    Transient and persistent expression of NT-3/BDNF mRNA in rat brain during postnatal development

    J. Neurosci.

    (1991)
  • Cited by (0)

    View full text