Early Regional Microglial Remodelling in the Hippocampus of the App^NL-G-F Alzheimer's Model

Neuropathol Appl Neurobiol. 2026 Jun;52(3):e70082. doi: 10.1111/nan.70082.

ABSTRACT

AIMS: Microglia undergo profound structural and functional changes during Alzheimer's disease, yet the earliest stages of morphological remodelling that occur prior to amyloid deposition remain poorly defined. We hypothesised that microglia in the hippocampus of App^NL-G-F mice would exhibit early, region-specific structural adaptations before local plaque formation, reflecting an initial phase of disease-associated structural remodelling.

METHODS: Two-month-old App^NL-G-F and wildtype mice were examined using high-resolution confocal microscopy of Iba1-labelled microglia in the dorsal CA1 apical field. Automated three-dimensional reconstructions were generated in Imaris, and quantitative morphometric analyses quantified cell density, Iba1 coverage, process topology and Sholl-based arbor complexity. Statistical analyses were performed using linear mixed-effects models incorporating sex as a fixed factor in all analyses.

RESULTS: Microglial density and total Iba1 coverage were unaffected in App^NL-G-F mice at this age. In contrast, Sholl analysis revealed significant genotype-dependent reductions in process intersections and total process length, accompanied by reduced individual-cell territorial coverage, indicating an early contraction of the surveillance arbor independent of cell number.

CONCLUSIONS: These findings demonstrate that hippocampal microglia in App^NL-G-F mice undergo an early, coordinated structural remodelling before local amyloid deposition becomes apparent. This preplaque adaptation defines an early structural remodelling of hippocampal microglia prior to evident local amyloid deposition, providing new insight into the earliest structural adaptations associated with neuroimmune engagement in AD pathogenesis.

PMID:42189000 | DOI:10.1111/nan.70082