Cell Reports · Jun 6, 2026

Impaired spatial coding and neuronal hyperactivity in the medial entorhinal cortex of aged APP knock-in mice

By Rodriguez GA, Aoun A, Rothenberg EF et al.

Advanced amyloid beta (Aβ) pathology is associated with aberrant neuronal network activity and cognitive impairment in preclinical Alzheimer's disease (AD) models. Here, we assess Aβ pathology's impact on spatial information processing in the medial entorhinal cortex (MEC) of 18-month AppNL-G-F/NL-G-F knock-in (APP KI) mice during exploration of open field arenas. Spatial information scores are decreased in APP KI MEC neurons versus age-matched controls. Border cell firing preferences are unstable across sessions and grid cell spatial periodicity is disrupted. Ratemap stability analysis using the Earth Mover's Distance indicates increased instability in spatially tuned APP KI neurons. Spatial decoding analysis indicates deficits in position and speed coding in APP KI mice across all comparisons. Additionally, APP KI mice display a mild hyperactive phenotype driven by narrow-spiking putative interneurons. These findings tie Aβ-associated dysregulation in neuronal firing to disruptions in spatial information processing that may underlie cognitive deficits associated with AD.

doi.org/10.1016/j.celrep.2026.117505Open accessPubMed 42250220Mechanisms