Loss of newborn neuron function accelerates neuroinflammation and amyloid accumulation via dentate gyrus circuit alteration in a mouse model of Alzheimer’s disease

Background Chronic neuroinflammation, characterized by persistent activation of microglia and astrocytes, is now recognized not merely as a bystander but as a fundamental driver of Alzheimer’s disease (AD) pathogenesis. Importantly, neuroinflammatory processes have been reported to be associated with disruptions in excitation–inhibition balance and network instability. Adult hippocampal newborn neurons play an important role in maintaining dentate gyrus (DG) circuit stability, and alterations in this neural population are among the earliest signs of AD pathology. We previously developed a conditional mouse model (NBN–TeTX) that selectively lose the function of hippocampal newborn neurons and demonstrated that these neurons are essential for maintaining hippocampal network balance. These observations raise the possibility that loss of newborn neuron function may contribute to neuroinflammatory responses through disruption of the DG circuit in AD pathology. Methods To investigate the impact of loss of newborn neuron function on neuroinflammation in AD model mice, we generated NBN-APP mice by crossing NBN-TeTX mice with APPswe/PS1dE9 (APP) mice. We performed snRNA-seq to characterize the transcriptomic landscape of the DG. Amyloid β (Aβ) deposition and glial morphological changes were assessed by histological analysis. Hippocampus-dependent cognitive function was evaluated using the Morris water maze and contextual fear conditioning tests. Results NBN-APP mice exhibited increased Aβ accumulation in the molecular layer of the DG compared with APP mice. Transcriptional analysis of the DG revealed an excitatory transcriptional signature in granule cells, together with increased disease-associated astrocytic signature ( p  = 3.08 × 10 ^⁻11 ) indicative of enhanced neuroinflammation in NBN-APP mice. Histological analyses confirmed increased abundance of astrocytes in the hippocampus, together with elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6. These alterations were associated with impairments in hippocampus-dependent cognitive function. Conclusion Our findings suggest that loss of hippocampal newborn neuron function in an AD mouse model may disrupt DG circuit balance, contributing to increased neuronal excitability and astrocyte reactivation. Increased abundance of reactive astrocytes was accompanied by enhanced neuroinflammatory responses in the hippocampus. These changes were associated with increased Aβ accumulation and cognitive impairment. Thus, impaired newborn neuron function may act as an upstream trigger of neuroinflammatory processes in AD, rather than merely representing a downstream consequence of disease progression.