{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:20:29Z","timestamp":1785406829463,"version":"3.56.0"},"reference-count":136,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004318","name":"Shimane University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004318","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01jaaym28","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. Its main pathological features are extracellular plaques composed of aggregated amyloid-\u03b2 (A\u03b2) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. The A\u03b2 hypothesis proposes that A\u03b2 accumulation is a key driver of AD, influencing tau pathology, neuroinflammation, and neurodegeneration. However, therapies that reduce A\u03b2 have shown limited clinical benefits. This suggests that the mechanisms underlying peptide-mediated modulation of AD pathology are much more complex. Both A\u03b2 and tau undergo various post-translational modifications (PTMs) that affect their structure, aggregation, and toxicity. In addition, these abnormal proteins are not efficiently cleared in AD, indicating dysfunction of the protein quality control (PQC) system that maintains proteostasis. Such abnormal PTMs and impaired PQC likely work together to drive disease progression, which may explain the limited success of A\u03b2-reduction therapies. In this review, we describe how major PTMs, including phosphorylation, ubiquitination, acetylation, glycosylation, and oxidation, regulate the pathological behavior of A\u03b2 and tau. We also discuss the role of the PQC systems in the pathology of AD. We propose that dysregulation of PTMs and PQC constitutes a convergent mechanism underlying AD pathogenesis. Therapeutic strategies targeting these processes may provide more effective and sustained disease modification than approaches focused solely on A\u03b2 reduction.<\/jats:p>","DOI":"10.3390\/ijms27104266","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:49:09Z","timestamp":1778572149000},"page":"4266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protein Modifications and Quality Control System: Target for Alzheimer\u2019s Disease Therapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1221-7787","authenticated-orcid":false,"given":"Abdullah Md.","family":"Sheikh","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9210-2949","authenticated-orcid":false,"given":"Shozo","family":"Yano","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan"},{"name":"The Center for Integrated Kidney Research and Advance (IKRA), Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shatera","family":"Tabassum","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2612-0225","authenticated-orcid":false,"given":"Jubo","family":"Bhuiya","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9280-8044","authenticated-orcid":false,"given":"Atsushi","family":"Nagai","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2019). 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