{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:27:35Z","timestamp":1791919655814,"version":"4.3.4"},"reference-count":245,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071214"],"award-info":[{"award-number":["82071214"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["OJQDSP2022011"],"award-info":[{"award-number":["OJQDSP2022011"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fund of Talent Launch Project of Oujiang Laboratory","award":["82071214"],"award-info":[{"award-number":["82071214"]}]},{"name":"Fund of Talent Launch Project of Oujiang Laboratory","award":["OJQDSP2022011"],"award-info":[{"award-number":["OJQDSP2022011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD), the most common type of dementia, is characterized by senile plaques composed of amyloid \u03b2 protein (A\u03b2) and neurofilament tangles derived from the hyperphosphorylation of tau protein. However, the developed medicines targeting A\u03b2 and tau have not obtained ideal clinical efficacy, which raises a challenge to the hypothesis that AD is A\u03b2 cascade-induced. A critical problem of AD pathogenesis is which endogenous factor induces A\u03b2 aggregation and tau phosphorylation. Recently, age-associated endogenous formaldehyde has been suggested to be a direct trigger for A\u03b2- and tau-related pathology. Another key issue is whether or not AD drugs are successfully delivered to the damaged neurons. Both the blood\u2013brain barrier (BBB) and extracellular space (ECS) are the barriers for drug delivery. Unexpectedly, A\u03b2-related SP deposition in ECS slows down or stops interstitial fluid drainage in AD, which is the direct reason for drug delivery failure. Here, we propose a new pathogenesis and perspectives on the direction of AD drug development and drug delivery: (1) aging-related formaldehyde is a direct trigger for A\u03b2 assembly and tau hyperphosphorylation, and the new target for AD therapy is formaldehyde; (2) nano-packaging and physical therapy may be the promising strategy for increasing BBB permeability and accelerating interstitial fluid drainage.<\/jats:p>","DOI":"10.3390\/pharmaceutics15041133","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T01:35:59Z","timestamp":1680572159000},"page":"1133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["New Insights into Alzheimer\u2019s Disease: Novel Pathogenesis, Drug Target and Delivery"],"prefix":"10.3390","volume":"15","author":[{"given":"Haishu","family":"Chen","sequence":"first","affiliation":[{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer\u2019s Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3156-3028","authenticated-orcid":false,"given":"Jinan","family":"Xu","sequence":"additional","affiliation":[{"name":"Cixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Albert, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiancheng","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute of Albert, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihao","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Albert, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Jiang","sequence":"additional","affiliation":[{"name":"Cixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangping","family":"Shentu","sequence":"additional","affiliation":[{"name":"Institute of Albert, Wenzhou Medical University, Wenzhou 325035, China"},{"name":"Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqian","family":"Tong","sequence":"additional","affiliation":[{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer\u2019s Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou 325035, China"},{"name":"Institute of Albert, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2016). 2016 Alzheimer\u2019s disease facts and figures. 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