Loss of Newborn Neuron Function Promotes Aβ Accumulation in an Alzheimer's Disease Mouse Model.

Abstract

Whether the loss of adult hippocampal newborn neuron (NBN) function contributes to Alzheimer's disease (AD) amyloid pathology remains unclear. Adult NBNs regulate dentate gyrus (DG) circuitry, and their decline has been observed during AD progression. To investigate their role, we generated NBN-APP mice by crossing APPswe/PS1dE9 mice with NBN-TeTX mice. Importantly, in vivo microdialysis in the DG molecular layer prior to plaque formation demonstrated that the loss of NBN function for 4 weeks, starting at 3 months of age (early phase), elevated soluble Aβ levels (p < 0.001). At this early phase, we also observed increased Aβ deposition in the lateral entorhinal cortex (p < 0.001). Furthermore, to evaluate chronic cumulative pathology, we extended the loss of NBN function to 8 weeks starting at 5 months of age (late phase), which resulted in enhanced Aβ plaque deposition in the DG molecular layer, widespread glial activation and inflammatory responses throughout the hippocampus, alongside cognitive alterations. Together, these findings demonstrate that the loss of NBN function consistently induces Aβ accumulation across both early and late phases, and is associated with glial activation, highlighting its contribution to AD pathology.