{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T06:08:14Z","timestamp":1788761294371,"version":"build-2803163510"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The reduction of \u03b17 nicotinic acetylcholine receptor (nAChR) in the hippocampus con-stitutes one of the neuropathological features observed in the brains of individuals with Alzheimer\u2019s disease (AD), and \u03b17 nAChR is crucial to cognitive process. However, studies involving \u03b17 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 \u03b17 nAChR deletion from embryonic stages. This limitation renders traditional knockout lines unable to recapitulate the adult-onset, hippocampus-restricted \u03b17 nAChR insufficiency characteristic of human AD, creating an unaddressed knowledge gap regarding whether isolated \u03b17 nAChR loss in mature hippocampal neurons independently drives AD-related neurodegeneration and cognitive dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To resolve this limitation, we established a spatially and temporally restricted knockdown mouse model\n                      <jats:italic>via<\/jats:italic>\n                      stereotaxic intrahippocampal injection of adeno-associated virus encoding\n                      <jats:italic>Chrna7<\/jats:italic>\n                      -targeted short hairpin RNA (shRNA) in 4-month-old mice. We assessed behavioral performance\n                      <jats:italic>via<\/jats:italic>\n                      open field test, novel object recognition test, Y-maze and Barnes maze 1\u00a0month post-viral delivery to quantify cognitive function; 2\u00a0months after injection, we harvested brain tissues to measure A\u03b2 deposition, tau hyperphosphorylation, neuronal loss, astrocytic and microglial activation using immunofluorescence staining, and performed transcriptome RNA sequencing to profile genome-wide transcriptional alterations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The knockdown of \u03b17 nAChR in the hippocampus of adult mice rapidly induced cognitive deficits, impairments in learning and memory, and led to the increase of amyloid-\u03b2 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our study demonstrates that selective depletion of hippocampal \u03b17 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 \u03b17 nAChR knockout animals by restricting receptor suppression exclusively to mature hippocampal neurons in post-developmental mice, closely recapitulating the spatial-temporal pattern of \u03b17 nAChR loss in human AD brains. Our work provides novel pharmacological insights into \u03b17 nAChR as a promising therapeutic target for AD pathological intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1929468","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:33:33Z","timestamp":1788759213000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Adult-onset hippocampal \u03b17 nicotinic acetylcholine receptor loss rapidly drives Alzheimer-like neuropathology in mice"],"prefix":"10.3389","volume":"17","author":[{"given":"Jun","family":"Li","sequence":"first","affiliation":[{"name":"Anhui Institute of Optics and Fine Mechanics, Hefei Institutes of Physical Science, Chinese Academy of Sciences","place":["Hefei, China"]},{"name":"University of Science and Technology of China","place":["Hefei, China"]},{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanglin","family":"Liu","sequence":"additional","affiliation":[{"name":"Anhui Institute of Optics and Fine Mechanics, Hefei Institutes of Physical Science, Chinese Academy of Sciences","place":["Hefei, China"]},{"name":"University of Science and Technology of China","place":["Hefei, China"]},{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Song","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Hou","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyuan","family":"Hu","sequence":"additional","affiliation":[{"name":"Anhui Institute of Optics and Fine Mechanics, Hefei Institutes of Physical Science, Chinese Academy of Sciences","place":["Hefei, China"]},{"name":"University of Science and Technology of China","place":["Hefei, China"]},{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1466166","DOI":"10.3389\/fnins.2025.1466166","article-title":"Abnormal response to chronic social defeat stress and fear extinction in a mouse model of Lynx2-based cholinergic dysregulation","volume":"19","author":"Anderson","year":"2025","journal-title":"Front. 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