Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (11): 3223-3224.doi: 10.4103/NRR.NRR-D-24-00751

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Targeting Epac2 and GluA3- containing AMPARs: a novel therapeutic strategy for Alzheimer’s disease

Tong Zhang, Martina Schmidt*   

  1. Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands (Zhang T, Schmidt M) School of Pharmacy, Tianjin Medical University, Tianjin, China (Zhang T)
  • Online:2025-11-15 Published:2025-02-23
  • Contact: Martina Schmidt, PhD, m.schmidt@rug.nl.
  • Supported by:
    We thank the Department of Molecular Pharmacology and Molecular Neurobiology for the support. This work was supported by Alzheimer Nederland grant [WE.03-2019-05] (to MS).

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease that manifests progressive decline in memory and cognition. In the early stage of AD, memory retrieval is impaired preceding memory acquisition and consolidation (Roy et al., 2016). Prior to the onset of symptoms, pathological amyloid-β (Aβ) plagues and tau protein tangles accumulate in extracellular and intracellular spaces, respectively, leading to neurodegeneration. Among these hallmark pathologies, Aβ is proposed to be the primary etiology by triggering a cascade of pathogenic events, including neuroinflammation, oxidative stress, tau hyperphosphorylation, synaptic/ neuronal dysfunction, and neuronal death (Zhang et al., 2023b). In the early stage of AD, the Aβ accumulation appears in the medial temporal lobe of the brain, such as the hippocampus and entorhinal cortex, which are crucial structures for memory and cognitive functions. Consequently, anti-amyloid therapy is a primary strategy against AD. A recent phase 3 trial reported that lecanemab, a newly developed monoclonal antibody against Aβ protofibrils, greatly decreased the makers of Aβ, tau, neuroinflammation, and neurodegeneration in cerebrospinal fluid, and moderately improved cognitive decline in patients with mild AD after 18-month treatment (van Dyck et al., 2023). The success of lecanemab supports the Aβ hypothesis and suggests Aβ pathology as a target for AD treatment.