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Targeting synapse function and loss for treatment of neurodegenerative diseases

Nature Reviews Drug Discovery volume 23, pages 23–42 (2024)Cite this article

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Abstract

Synapse dysfunction and loss are hallmarks of neurodegenerative diseases that correlate with cognitive decline. However, the mechanisms and therapeutic strategies to prevent or reverse synaptic damage remain elusive. In this Review, we discuss recent advances in understanding the molecular and cellular pathways that impair synapses in neurodegenerative diseases, including the effects of protein aggregation and neuroinflammation. We also highlight emerging therapeutic approaches that aim to restore synaptic function and integrity, such as enhancing synaptic plasticity, preventing synaptotoxicity, modulating neuronal network activity and targeting immune signalling. We discuss the preclinical and clinical evidence for each strategy, as well as the challenges and opportunities for developing effective synapse-targeting therapeutics for neurodegenerative diseases.

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Fig. 1: Synaptic structure and pathology in neurodegeneration.
Fig. 2: Therapeutic approaches targeting synapse function and loss.
Fig. 3: Key pathways mediating axonal and presynaptic degeneration.
Fig. 4: Approaches for quieting hyperactive networks.
Fig. 5: Major regulators of microglial and astrocytic synapse phagocytosis.

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Acknowledgements

The authors thank C. Bohlen, F. Hinz, M.-C. Tsai, F. Yeh, D. Gray and M. Figley for the critical reading of the manuscript.

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Authors and Affiliations

  1. Vigil Neuroscience, Cambridge, MA, USA

    Borislav Dejanovic

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Morgan Sheng

  3. Department of Neuroscience, Genentech, South San Francisco, CA, USA

    Jesse E. Hanson

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  1. Borislav Dejanovic
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  2. Morgan Sheng
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The authors contributed equally to all aspects of the article.

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Correspondence to Borislav Dejanovic or Jesse E. Hanson.

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Competing interests

B.D. is a full-time employee of Vigil Neuroscience. M.S. is scientific cofounder and member of the scientific advisory board of Neumora Therapeutics and serves on the scientific advisory board of Biogen, Vanqua Bio, ArcLight Therapeutics, Proximity Therapeutics and Cerevel Therapeutics. J.E.H. is a full-time employee of Genentech, a member of the Roche Group.

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Glossary

Astrocytes

A type of glial cell located in the CNS, responsible for a multitude of tasks such as supplying neurons with nutrients, managing the function of synapses, maintaining the balance of extracellular ions and chemicals and preserving the structural integrity of the blood–brain barrier.

Interneurons

Inhibitory neurons that form nodes within neural circuitry and regulate neuronal activity by releasing the neurotransmitter GABA, which inhibits firing of other neurons.

Medial ganglionic eminence

(MGE). Structure in the developing nervous system that produces inhibitory interneurons, which disperse widely throughout the brain.

Membrane attack complex

A complex of complement proteins that forms cytolytic pores in the plasma membrane of targeted cells such as pathogens.

Microglia

Resident immune cells of the CNS that respond to pathogens and damage and can engage in phagocytosis of protein aggregates, cellular structures and other substrates.

Neurofilament light

Neuronal structural protein that is located primarily within myelinated axons.

Synaptic plasticity

The ability of synapses to modify their strength over time in response to differing levels of activity.

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Dejanovic, B., Sheng, M. & Hanson, J.E. Targeting synapse function and loss for treatment of neurodegenerative diseases. Nat Rev Drug Discov 23, 23–42 (2024). https://doi.org/10.1038/s41573-023-00823-1

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