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  • Review Article
  • Published:

BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases

Nature Reviews Neuroscience volume 14, pages 401–416 (2013)Cite this article

Subjects

Key Points

  • Scientific advancement in neuroscience has not been effectively translated into therapies for neurological diseases. In general, 'toxin reducing' approaches (for example, lowering amyloid-β (Aβ)) thus far have not resulted in halting or delaying disease progression. A paradigm shift in the discovery of disease-modifying therapies for neurological diseases is urgently needed.

  • For neurodegenerative diseases, targeting the pathophysiology rather than the pathogenesis may be more effective to achieve therapeutic intervention. The toxin reducing approach may work if treatment starts very early on in the disease process.

  • Synapse degeneration is a major pathophysiological feature that correlates with disease progression in multiple neurodegenerative diseases. Neuronal loss is irreversible, whereas synapses can be repaired and regenerated.

  • Three aspects of synaptic physiology can be targeted: synaptic transmission, synaptic plasticity and synaptic growth. For disease-modifying therapy, synaptic plasticity and, more importantly, synaptic growth should be targeted.

  • Brain-derived neurotrophic factor (BDNF) is an exemplar of synaptic repair therapy, as it regulates all three aspects of synaptic physiology. It protects and repairs existing synapses and stimulates new synapse formation, even in the presence of various toxins.

  • In humans, the BDNF Val66Met polymorphism in conjunction with high Aβ deposits confers faster decline in Alzheimer's disease endophenotypes such as episodic memory and hippocampal volume, and therefore could be considered as a patient stratification strategy for clinical trials with enhanced sensitivity and robustness.

  • Success of a 'synaptic repair' therapy depends on whether synaptic dysfunction and synaptic repair and/or regeneration can be measured in the clinic. Efforts should be made to develop sensitive and reliable methodologies to measure synaptic function in humans in vivo.

  • Opportunities and challenges in developing BDNF–TRKB pathway-based therapies, including delivery, are discussed.

  • A combination of synaptic therapy and a more reliable and sensitive method (or methods) to measure synaptic changes may pave the way for developing disease-modifying medicines for debilitating neurological diseases. This Review highlights recent discoveries, discusses emerging concepts and proposes synapse-based therapies for treating neurodegenerative diseases.

Abstract

Increasing evidence suggests that synaptic dysfunction is a key pathophysiological hallmark in neurodegenerative disorders, including Alzheimer's disease. Understanding the role of brain-derived neurotrophic factor (BDNF) in synaptic plasticity and synaptogenesis, the impact of the BDNF Val66Met polymorphism in Alzheimer's disease-relevant endophenotypes — including episodic memory and hippocampal volume — and the technological progress in measuring synaptic changes in humans all pave the way for a 'synaptic repair' therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis. This article reviews the key issues in translating BDNF biology into synaptic repair therapies.

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Figure 1: Disease progression and its underlying pathogenic and pathophysiological processes.
Figure 2: Schematic representation of temporal events in neurodegenerative diseases.
Figure 3: BDNF regulates synaptic transmission, synaptic plasticity and synaptic growth.

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Acknowledgements

We thank our colleagues at GlaxoSmithKline and at various academic institutes for their critical comments and suggestions during our discussions on the topic.

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Authors and Affiliations

  1. GlaxoSmithKline, R&D China, Shanghai, 201203, China

    Bai Lu, Guhan Nagappan, Xiaoming Guan & Paul Wren

  2. Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Cambridge, CB2 2GG, UK

    Pradeep J. Nathan

  3. Department of Psychiatry, Brain Mapping Unit, University of Cambridge, Cambridge, CB2 0SZ, UK

    Pradeep J. Nathan

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  1. Bai Lu
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  2. Guhan Nagappan
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  3. Xiaoming Guan
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Correspondence to Bai Lu.

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PowerPoint slides

Glossary

Disease-modifying therapies

Medical therapies that address the cause of the disease either directly or indirectly and thereby modify the course of the disease: that is, slow down, halt or reverse disease progression.

Symptomatic treatment

A medical therapy that only relieves or controls the disease symptoms but not its cause per se.

Phase III

A trial conducted to gather new information about the safety and effectiveness of a particular therapy in a larger group of patients than that used in Phase II clinical trials.

Synaptic plasticity

Activity-dependent modulation of synaptic structure and/or function.

Synaptogenesis

The formation of new synapses between neurons, and the maturation and stabilization of existing synapses. It is also termed synaptic growth.

Early-phase LTP

(E-LTP). Early-phase long-term potentiation (LTP) is a sustained increase in synaptic efficacy that is induced by brief, high-frequency tetanic stimulation and lasts for 1–2 hours. It does not require gene transcription or protein synthesis.

Late-phase LTP

(L-LTP). Late-phase long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy that is induced by strong, multiple tetanic stimuli and lasts for several hours or even days. It is both transcription- and translation-dependent and is often accompanied by morphological changes at the stimulated synapses.

Paired associative stimulation

A neurophysiological paradigm that involves stimulation of the median peripheral nerve followed by transcranial magnetic stimulation of the contralateral motor cortex. This paradigm has been successfully used to induce plasticity changes in the human motor cortex.

Gene dosage

A linear relationship between the number of genes (or alleles), the gene (or allele) product and the resulting effect (the phenotype).

Epistatic

The effect of one gene or gene product influencing the effect of other genes or gene products.

Endophenotypes

Intrinsic phenotypes that are relevant to a disease but not evident without a test. A good endophenotype must be tightly associated with the disease and display familial association even in non-diseased relatives with a higher odds ratio than in the general population.

Phase I

Phase I trials are typically conducted in healthy volunteers or in patients in a closely monitored clinic to evaluate safety, tolerability and pharmacokinetics of a new investigational drug.

Forced vital capacity

The amount of air that can be forcibly exhaled from the lungs after a deep breath, which can be measured with a spirometer.

Phase II

A trial conducted primarily to evaluate the effectiveness of a drug in people who have a certain disease or condition. Safety continues to be evaluated in the clinical setting. Initial Phase II efficacy studies are also referred to as proof-of-concept studies.

ALSFRS

Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R is the revised version) is a validated measure (scores 0–48) that aids the assessment of disability of the patients with motor neuron diseases based on a questionnaire that asks about daily activities and how much help the patients need along with disease-specific symptoms.

Nanoparticle

A microscopic particle with a diameter of less than 100 nm. Here, it refers to the liposomes or exosomes that carry drug substances into the brain.

Trojan horse

A strategy to deliver drugs to target sites that are normally inaccessible. The drug is fused to a molecule or encapsulated in a cell or nanoparticle that can readily cross the blood–brain barrier.

Nose-to-brain

Delivery or transport of drugs, cells or cargoes into the brain intranasally through the olfactory or trigeminal neuronal pathway. This delivery route limits systemic exposure and bypasses the blood–brain barrier.

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Lu, B., Nagappan, G., Guan, X. et al. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14, 401–416 (2013). https://doi.org/10.1038/nrn3505

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