BACKGROUND: Hippocampal dysfunction induced by soluble amyloid-β oligomers (oAβ) is an early neuropathological hallmark of Alzheimer's disease (AD). oAβ shifts hippocampal synaptic-plasticity induction threshold facilitating long-term depression (LTD) instead of long-term potentiation (LTP, the functional basis of memory), thereby leading to memory deficits in early AD-like amyloidosis mouse models. In this regard, the spatial distribution of the underlying synaptic-plasticity/memory proteome changes in the hippocampus, and potential sex differences, remain unknown. Here we postulated that some protein changes related to synaptic-plasticity and memory may be unique to sex and/or specific to the dorsal or ventral hippocampus -as both regions have distinct functionality and connectivity-, potentially providing sex- and spatial-specific proteomic phenotypes for early AD-amyloidosis interventions. METHODS: An innovative spatial-resolution proteomics study was performed to map whole hippocampal proteome distribution using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry. For this purpose, sixteen adult male and female mouse brains intracerebroventricularly injected with oAβ(1-42)/vehicle were analyzed. MALDI-imaging RapifleXTM-MALDI-TissuetyperTM TOF/TOF mass spectrometer was used, followed by traditional tandem mass spectrometry (MS/MS) for precise protein identification on tissue. RESULTS: 34 proteins showed significant differences in expression levels due to treatment, sex, or hippocampal location among 234 peptides initially detected; and displayed significant protein-protein interaction (PPI), indicating main functional relationship to LTP/LTD pathways and memory. Thus, 14 proteins related to synaptic-plasticity and/or AD were further studied, showing that most modulated glycogen synthase kinase-3β (GSK-3β), a protein widely involved in synaptic-plasticity induction threshold regulation towards LTD. Accordingly, hippocampal GSK-3β was found to be overactivated in AD-like amyloidosis mice. CONCLUSIONS: We show for the first-time specific sex-dependent synaptic-plasticity proteome changes in dorsal/ventral hippocampi that modulate GSK-3β activity. These findings provide new insight into the early amyloidosis pathogenesis in AD and offer valuable, unique proteomic phenotypes as potential biomarkers and targets for early diagnosis and therapy in both sexes.