Abstract: Alzheimer’s disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks, leading to aberrant homeostatic synaptic plasticity. AD has progressively been recognized as synaptopathy and synaptic dysfunction has been identified as a key component of its pathogenesis (Schirinzi et al., 2020). Synapttc dysfunctton is believed to precede synapse loss, a primary biological correlate of cognitive decline in AD, inevitably associated with neuronal death. The mechanism underlying synapse failure should depend on the specific molecular alterattons associated with the affected neuronal circuit, making it a crucial stage in AD pathogenesis. Despite the numerous dysfuncttons described in the AD brain, their underlying speciffc molecular alterattons remain unknown. Here, our goal is to highlight recent investigations focusing on the influence of amyloid-beta pathology on the nanoarchitecture of crittcal synapttc signaling proteins. Indeed, synapttc communicatton hinges on the precise molecular organization of specific signaling proteins, encompassing their density, distribution, and stoichiometry associated with each type of synapse. Consequently, the disruptton of such precise molecular organizatton can modify synaptic transmission, thereby altering neural circuits and ultimately leading to neuronal loss, contributtng to neurodegeneratton. Therefore, prevalent pathological features of neurodegenerative diseases include the loss of specific populations of synapses. For example, the pathological hallmark of AD encompasses the loss of excitatory synapses in the CA1 area of the hippocampus, observed in the early stages of the disease in both patients and animal models (Montero-Crespo et al., 2021). Importantly, we recently reported nanoscale alterations on the two-dimensional distribution of the G proteingated inwardly rectifying K+ (GIRK) channels and their spatial interplay with the gammaaminobutyric acid G protein-coupled receptor type B (GABAB receptor) in hippocampal CA1 pyramidal neurons from the APP/PS1 mouse model of AD (Martín-Belmonte et al., 2022). Overall, this nuanced exploration of nanoscale alterations of synapses on the APP/PS1 mouse provides valuable insights into the early pathological features of AD and may offer new strategies for therapeutic interventton.