{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:17:34Z","timestamp":1780593454309,"version":"3.54.1"},"reference-count":26,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,15]]},"abstract":"<jats:p>Studies of amyloid-\u03b2 (A\u03b2) in Alzheimer\u2019s disease pathology have revealed the peptide\u2019s complex roles in synaptic function. The study by Siddu et al. in this issue clarifies the contexts in which A\u03b2 peptides may be synaptogenic or synaptotoxic. This commentary integrates the study\u2019s major findings with the salient findings of others that, over recent years, have redefined A\u03b2 from a troublesome waste product into a physiological agent of the innate immune response and a modulator of synaptic homeostasis. Convergent evidence demonstrates how free, nonaggregated A\u03b2 supports synaptic structure and activity, whereas oligomeric assemblies enact an adaptive brake on excitatory drive that can become maladaptive with age and inflammation. This redefined perspective on A\u03b2 function emphasizes an evolutionarily conserved feedback loop linking neuronal activity, amyloid generation, and synaptic tuning that protects energy balance under stress but, when dysregulated, promotes proteostatic failure, persistent neuroinflammation, and network dysfunction characteristic of Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1172\/jci200393","type":"journal-article","created":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T19:00:54Z","timestamp":1765738854000},"source":"Crossref","is-referenced-by-count":2,"title":["From synaptic guardian to neurodegenerative culprit: rewiring the amyloid-\u03b2 feedback loop in Alzheimer\u2019s disease"],"prefix":"10.1172","volume":"135","author":[{"given":"Joachim","family":"Herz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI193407"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2433"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2692-08.2008"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.04.024"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09114-z"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.10.035"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00124-7"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nature07761"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nm1782"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.10.028"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)32449-3"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg1925"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914984107"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2017.08.003"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.72034"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.40048"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80861-2"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209205200"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02318-3"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.11.043"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.06.3040"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)70016-5"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.70176"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-025-02096-8"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600824"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/200393\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:06:32Z","timestamp":1779210392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/200393"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":26,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,10,23]]},"published-print":{"date-parts":[[2025,12,15]]}},"alternative-id":["10.1172\/JCI200393"],"URL":"https:\/\/doi.org\/10.1172\/jci200393","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]},"article-number":"e200393"}}