Adult-onset hippocampal α7 nicotinic acetylcholine receptor loss rapidly drives Alzheimer-like neuropathology in mice

Introduction The reduction of α7 nicotinic acetylcholine receptor (nAChR) in the hippocampus con-stitutes one of the neuropathological features observed in the brains of individuals with Alzheimer’s disease (AD), and α7 nAChR is crucial to cognitive process. However, studies involving α7 nAChR knockout mice have not demonstrated any abnormal brain structure or damage to hippocampal neurons, a discrepancy likely driven by widespread developmental compensatory signaling reprogramming triggered by permanent whole-body α7 nAChR deletion from embryonic stages. This limitation renders traditional knockout lines unable to recapitulate the adult-onset, hippocampus-restricted α7 nAChR insufficiency characteristic of human AD, creating an unaddressed knowledge gap regarding whether isolated α7 nAChR loss in mature hippocampal neurons independently drives AD-related neurodegeneration and cognitive dysfunction. Methods To resolve this limitation, we established a spatially and temporally restricted knockdown mouse model via stereotaxic intrahippocampal injection of adeno-associated virus encoding Chrna7 -targeted short hairpin RNA (shRNA) in 4-month-old mice. We assessed behavioral performance via open field test, novel object recognition test, Y-maze and Barnes maze 1 month post-viral delivery to quantify cognitive function; 2 months after injection, we harvested brain tissues to measure Aβ deposition, tau hyperphosphorylation, neuronal loss, astrocytic and microglial activation using immunofluorescence staining, and performed transcriptome RNA sequencing to profile genome-wide transcriptional alterations. Results The knockdown of α7 nAChR in the hippocampus of adult mice rapidly induced cognitive deficits, impairments in learning and memory, and led to the increase of amyloid-β levels, Tau protein aggregation, neuronal damage, and the activation of astrocytes and microglia. Transcriptomic analysis revealed that the differentially expressed genes were significantly enriched in pathways related to inflammatory signaling. Discussion Our study demonstrates that selective depletion of hippocampal α7 nAChR in adult mice is sufficient to trigger a spectrum of AD-like pathological alterations. Importantly, our AAV-mediated region-specific knockdown paradigm fully eliminates the developmental compensatory bias inherent to constitutive global α7 nAChR knockout animals by restricting receptor suppression exclusively to mature hippocampal neurons in post-developmental mice, closely recapitulating the spatial-temporal pattern of α7 nAChR loss in human AD brains. Our work provides novel pharmacological insights into α7 nAChR as a promising therapeutic target for AD pathological intervention.