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The synapse as a treatment avenue for Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder with devastating symptoms, including memory impairments and cognitive deficits. Hallmarks of AD pathology are amyloid-beta (Aβ) deposition forming neuritic plaques and neurofibrillary tangles (NFTs). For many years, AD drug development has mainly focused on directly targeting the Aβ aggregation or the formation of tau tangles, but this disease has no cure so far. Other common characteristics of AD are synaptic abnormalities and dysfunctions such as synaptic damage, synaptic loss, and structural changes in the synapse. Those anomalies happen in the early stages of the disease before behavioural symptoms have occurred. Therefore, better understanding the mechanisms underlying the synaptic dysfunction found in AD and targeting the synapse, especially using early treatment windows, can lead to finding novel and more effective treatments that could improve the lives of AD patients. Researchers have recently started developing different disease-modifying treatments targeting the synapse to rescue and prevent synaptic dysfunction in AD. The main objectives of these new strategies are to halt synaptic loss, strengthen synaptic connections, and improve synaptic density, potentially leading to the rescue or prevention of cognitive impairments. This article aims to address the mechanisms of synaptic degeneration in AD and discuss current strategies that focus on the synapse for AD therapy. Alzheimer’s disease (AD) is a neurodegenerative disorder that significantly impairs memory and causes cognitive and behavioural deficits. Scientists worldwide have tried to find a treatment that can reverse or rescue AD symptoms, but there is no cure so far. One prominent characteristic of AD is the brain atrophy caused by significant synaptic loss and overall neuronal damage, which starts at the early stages of the disease before other AD hallmarks such as neuritic plaques and NFTs. The present review addresses the underlying mechanisms behind synaptic loss and dysfunction in AD and discusses potential strategies that target the synapse.

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Fig. 1: Oligomeric Aβ and phosphorylated tau induce neural toxicity causing synaptic loss and dysfunction.
Fig. 2: General representation of the role of microglia, astrocytes and ApoE isoform on abnormal synaptic pruning and synaptic dysfunction.

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Funding

This work was supported by the Key Laboratory of Alzheimer’s Disease Of Zhejiang Province, the grants from the Canadian Institutes of Health Research (CIHR) Project Grant PJT-166127 to WS, the National Natural Science Foundation of China (No. 81801091) to LP, and the Natural Science Foundation of Shandong Province of China (No. ZR2019BH076) to LP. WS was the holder of the Tier 1 Canada Research Chair in Alzheime’s Disease, and IBL is supported by the UBC Four Year Fellowship and the Jock & Irene Graham Brain Research Endowment.

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  1. These authors contributed equally: Lin Peng, Isabel Bestard-Lorigados.

Authors and Affiliations

  1. Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, China

    Lin Peng & Weihong Song

  2. Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, BC, Canada

    Lin Peng, Isabel Bestard-Lorigados & Weihong Song

  3. Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China

    Weihong Song

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All authors were involved in literature search and writing of the article. WS supervised the project.

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Peng, L., Bestard-Lorigados, I. & Song, W. The synapse as a treatment avenue for Alzheimer’s Disease. Mol Psychiatry 27, 2940–2949 (2022). https://doi.org/10.1038/s41380-022-01565-z

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