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What’s hAPPening at synapses? The role of amyloid β-protein precursor and β-amyloid in neurological disorders

Abstract

Accumulating evidence suggests that dysregulated levels of amyloid β-protein precursor (APP) and its catabolites contribute to the impaired synaptic plasticity and seizure incidence observed in several neurological disorders, including Alzheimer’s disease, fragile X syndrome, Down’s syndrome, autism, epilepsy and Parkinson’s disease as well as in brain injury. This review article summarizes what is known regarding the synaptic synthesis, processing and function of APP and amyloid-beta (Aβ), as well as discusses how these proteins could contribute to the altered synaptic plasticity and pathology of the aforementioned disorders. In addition, APP and its proteolytic fragments are emerging as biomarkers for neurological health, and pharmacological interventions that modulate their levels, such as secretase inhibitors, passive immunotherapy against Aβ and mGluR5 antagonists, are reviewed.

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Acknowledgements

The author thanks Dr Pamela Westmark and the reviewers for critical examination of the manuscript. Dr Westmark’s research has been funded by FRAXA Research Foundation, The Alzheimer’s Drug Discovery Foundation, Lundbeck Research USA, Inc. and Merz Pharmaceuticals GmbH.

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Westmark, C. What’s hAPPening at synapses? The role of amyloid β-protein precursor and β-amyloid in neurological disorders. Mol Psychiatry 18, 425–434 (2013). https://doi.org/10.1038/mp.2012.122

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Keywords

  • amyloid
  • APP
  • mGluR5
  • β-secretase
  • seizure
  • synapse

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