{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:19:46Z","timestamp":1783660786558,"version":"3.55.0"},"reference-count":119,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Previous simulations of Hebbian associative memory models inspired the malignant synaptic growth hypothesis of Alzheimer's disease (AD), which suggests that cognitive impairments arise due to runaway synaptic modification resulting from poor separation between encoding and retrieval.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We computationally model presynaptic inhibition by the recently identified interaction of soluble amyloid precursor protein alpha (sAPP\u03b1) with\n                      <jats:italic>\u03b3<\/jats:italic>\n                      \u2010aminobutyric acid type B receptor (GABA\n                      <jats:sub>B<\/jats:sub>\n                      R) as one potential biological mechanism that can enhance separation between encoding and retrieval.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Simulations predict that the dual effect of sAPP\u03b1 on long\u2010term potentiation and presynaptic inhibition of glutamatergic synapses maintains effective associative memory function and prevents runaway synaptic modification. Moreover, computational modeling predicts that sAPP\u03b1, which interacts with the 1a isoform of GABA\n                      <jats:sub>B<\/jats:sub>\n                      R, is more effective than the GABA\n                      <jats:sub>B<\/jats:sub>\n                      R agonist baclofen at stabilizing associative memory.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      Molecular mechanisms that enhance presynaptic inhibition, such as sAPP\u03b1\u2010GABA\n                      <jats:sub>B<\/jats:sub>\n                      R1a signaling, are potential therapeutic targets for preventing cognitive impairments in AD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Computational modeling of Hebbian associative memory provides a framework for understanding the functional basis of Alzheimer's disease.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Soluble amyloid precursor protein (sAPP\u03b1) presynaptic activation of \u03b3\u2010aminobutyric acid B (GABA\n                            <jats:sub>B<\/jats:sub>\n                            ) receptors prevents runaway synaptic modification in associative memory models.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>sAPP\u03b1 is more effective than baclofen at stabilizing associative memory.<\/jats:p>\n                        <\/jats:list-item>\n                      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