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Brain-derived neurotrophic factor in neurodegenerative diseases

Abstract

Changes in the levels and activities of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), have been described in a number of neurodegenerative disorders, including Huntington disease, Alzheimer disease and Parkinson disease. It is only in Huntington disease, however, that gain-of-function and loss-of-function experiments have linked BDNF mechanistically with the underlying genetic defect. Altogether, these studies have led to the development of experimental strategies aimed at increasing BDNF levels in the brains of animals that have been genetically altered to mimic the aforementioned human diseases, with a view to ultimately influencing the clinical treatment of these conditions. In this article, we will review the current knowledge about the involvement of BDNF in a number of neurodegenerative diseases, with particular emphasis on Huntington disease, and will provide the rationale for and discuss the problems in proposing BDNF treatment as a beneficial and feasible therapeutic approach in the clinic.

Key Points

  • Brain-derived neurotrophic factor (BDNF) levels are reduced in the brains of patients with Alzheimer disease, Parkinson disease and Huntington disease

  • Data on BDNF in individuals affected by Alzheimer disease or Parkinson disease require further validation

  • Experiments performed in a range of Huntington disease animal models and in human tissue show reduced cortical BDNF mRNA and protein levels with respect to controls

  • BDNF trafficking is reduced in the presence of the Huntington disease mutation in experiments conducted in vitro

  • A mechanistic link has been established between wild-type huntingtin and gene transcription and intracellular transport of BDNF

  • Strategies for 'BDNF therapies' include upregulating BDNF levels by gene or protein delivery, or through small molecules targeting BDNF production, and increasing BDNF signaling using BDNF mimetics

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Figure 1: Regulation of BDNF gene transcription by huntingtin.
Figure 2: The role of huntingtin in the intracellular transport of BDNF vesicles.
Figure 3: Experimental therapeutic strategies for restoring BDNF function in neurodegenerative diseases.

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Acknowledgements

The work of the authors described in this Review was supported by the Huntington Disease Society of America (USA), Telethon (Italy), the Hereditary Disease Foundation (USA), the HighQ/CHDI Foundation (USA), Fondazione Cariplo (Italy), Ministero dell'Istruzione dell'Università e della Ricerca (Italy), Ministero della Salute (Italy), NeuroNE (Sixth Framework Programme, European Union, LSHM-CT-2004-512039) and STEM-HD (Sixth Framework Programme, European Union, LSHB-CT-2006-037349) (E. Cattaneo) and by Conferenza dei Rettori delle Università Italiane (Italy) (C. Zuccato).

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Correspondence to Elena Cattaneo.

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Zuccato, C., Cattaneo, E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5, 311–322 (2009). https://doi.org/10.1038/nrneurol.2009.54

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