Journal of dementia and alzheimer's disease最新文献

{"title":"Low Brain Levels of Dietary Polyphenols and Their Conjugates: Reassessing Mechanisms of Alzheimer's Disease Prevention.","authors":"Roshni Sharma, Kristina Shkirkova, William J Mack, Rayudu Gopalakrishna","doi":"10.3390/jdad3020027","DOIUrl":"10.3390/jdad3020027","url":null,"abstract":"<p><p>Dietary polyphenols such as quercetin, resveratrol, and (-)-epigallocatechin-3-gallate (EGCG) have shown neuroprotective effects in epidemiologic and experimental studies of Alzheimer's disease (AD), although clinical evidence remains limited. This review highlights the importance of investigating glucuronide and sulfate conjugates of these polyphenols, as well as their intestinal microbial metabolites, at bioavailable low nanomolar concentrations, particularly those capable of reaching the brain. Although many in vitro studies use micromolar concentrations of aglycones, the relevance of such concentrations to neuroprotection remains uncertain. While polyphenols are redox-sensitive, their direct antioxidant or prooxidant effects may be limited at nanomolar concentrations. Instead, their neuroprotective actions appear to be mediated through high-affinity interactions with molecular targets such as the 67-kDa laminin receptor (67LR). This receptor binds both aglycones and conjugates at low nanomolar concentrations through a peptide G region containing glycosaminoglycan- and palindromic sequence-related motifs. The same region also binds the prion-amyloid-β complex, suggesting that polyphenols may antagonize amyloid-β binding and thereby prevent its neurotoxicity. The peptide G region may also function as a redox sensor. Binding of polyphenols to 67LR activates cAMP signaling and downstream neuroprotective pathways involving CREB, SIRT1, and protein phosphatase 2A. In addition, nanomolar concentrations of resveratrol and quercetin inhibit quinone reductase 2, an enzyme associated with cognitive decline and reported to be elevated in AD. Given their low bioavailability in the brain and their distinct molecular targets, combining multiple polyphenols at low doses may produce additive or synergistic effects, enhance efficacy, and minimize potential toxicity in the prevention of AD.</p>","PeriodicalId":521041,"journal":{"name":"Journal of dementia and alzheimer's disease","volume":"3 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148723927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Target the Heart: A New Axis of Alzheimer's Disease Prevention.","authors":"Lawrence I Heller, Allison S Lowe, Thaís Del Rosario Hernández, Sayali V Gore, Mallika Chatterjee, Robbert Creton","doi":"10.3390/jdad2020010","DOIUrl":"10.3390/jdad2020010","url":null,"abstract":"<p><strong>Background/objective: </strong>Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer's disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer's disease.</p><p><strong>Methods: </strong>Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin.</p><p><strong>Results: </strong>Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin-NFAT pathway, like cyclo-sporine A, providing a potential mechanism.</p><p><strong>Conclusions: </strong>Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer's disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer's disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration.</p>","PeriodicalId":521041,"journal":{"name":"Journal of dementia and alzheimer's disease","volume":"2 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic Reticulum Stress in Neurodegenerative Diseases.","authors":"Syed-Abdul-Moiz Hasan, Antonisamy William James, Farzeen M Fazili, Samiha Tarabishi, Namir M Sheikh, Zahoor A Shah","doi":"10.3390/jdad1020006","DOIUrl":"10.3390/jdad1020006","url":null,"abstract":"<p><p>Endoplasmic reticulum (ER) stress is a detrimental cellular phenomenon in the cells and is activated by the accumulation of unfolded or misfolded proteins in the ER. The unfolded protein accumulation activates the unfolded protein response (UPR), an adaptive mechanism designed to mitigate cellular stress by enhancing the ER's protein-folding capacity and protecting cells from apoptotic stimuli in neuroinflammation and neurodegenerative diseases. However, chronic ER stress and prolonged activation of the UPR can have adverse effects, including the activation of pro-apoptotic and inflammatory signaling pathways, which contribute to the development and progression of neurodegenerative disorders. Neurodegenerative diseases are complex and devastating conditions with underlying pathogenesis that are not fully understood. Genetic mutations leading to the accumulation of misfolded or phosphorylated tau proteins and amyloid-beta in the ER can induce ER stress, resulting in neuroinflammation and neuronal death. Several studies have reported the involvement of increased ER stress and UPR signaling proteins in the pathogenesis and progression of neurodegenerative diseases. Thus, inhibiting ER stress and neuroinflammation and targeting their associated signaling pathways represent a significant area of research interest. This review discusses the critical signaling molecules involved in ER stress, their mechanisms in the progression of neurodegenerative diseases, and the latest developments in the available ER stress inhibitors. Despite the extensive development of ER stress inhibitors over the years, only a limited number have been approved as pharmaceutical drugs. There remains a critical need for effective ER stress inhibitors to provide efficient treatments for neurodegenerative diseases, including Alzheimer's disease.</p>","PeriodicalId":521041,"journal":{"name":"Journal of dementia and alzheimer's disease","volume":"1 2","pages":"87-97"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147501620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}