The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation
Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer’s disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechani...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2025-08-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/99462 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849240005698912256 |
|---|---|
| author | Weiwei Qi Yanlan Long Ziming Li Zhen Zhao Jinhui Shi Wanting Xie Laijian Wang Yandan Tan Ti Zhou Minting Liang Ping Jiang Bin Jiang Xia Yang Guoquan Gao |
| author_facet | Weiwei Qi Yanlan Long Ziming Li Zhen Zhao Jinhui Shi Wanting Xie Laijian Wang Yandan Tan Ti Zhou Minting Liang Ping Jiang Bin Jiang Xia Yang Guoquan Gao |
| author_sort | Weiwei Qi |
| collection | DOAJ |
| description | Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer’s disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD. |
| format | Article |
| id | doaj-art-4e90bb5c1d144fd299fd4b7b5af91afb |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-4e90bb5c1d144fd299fd4b7b5af91afb2025-08-20T04:00:45ZengeLife Sciences Publications LtdeLife2050-084X2025-08-011310.7554/eLife.99462The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylationWeiwei Qi0Yanlan Long1https://orcid.org/0000-0001-5164-4736Ziming Li2Zhen Zhao3Jinhui Shi4Wanting Xie5Laijian Wang6Yandan Tan7Ti Zhou8https://orcid.org/0000-0001-8517-5405Minting Liang9Ping Jiang10Bin Jiang11Xia Yang12https://orcid.org/0000-0003-1668-8121Guoquan Gao13https://orcid.org/0000-0001-8996-1470Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, ChinaGuangdong Province Key Laboratory of Brain Function and Disease, School of Medicine, Sun Yat-sen University, Shenzhen, ChinaDepartment of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Brain Function and Disease, School of Medicine, Sun Yat-sen University, Shenzhen, ChinaDepartment of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Clinical Medical Laboratory, Guangzhou First People Hospital, School of Medicine, South China University of Technology, Guangzhou, ChinaGuangdong Province Key Laboratory of Brain Function and Disease, School of Medicine, Sun Yat-sen University, Shenzhen, ChinaDepartment of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; China Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, ChinaDepartment of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products (Sun Yat-sen University), Guangzhou, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-sen University Guangzhou, Guangdong, ChinaAccumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer’s disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD.https://elifesciences.org/articles/99462Alzheimer's diseaseKallistatinAβ42BACE1diabetes |
| spellingShingle | Weiwei Qi Yanlan Long Ziming Li Zhen Zhao Jinhui Shi Wanting Xie Laijian Wang Yandan Tan Ti Zhou Minting Liang Ping Jiang Bin Jiang Xia Yang Guoquan Gao The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation eLife Alzheimer's disease Kallistatin Aβ42 BACE1 diabetes |
| title | The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation |
| title_full | The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation |
| title_fullStr | The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation |
| title_full_unstemmed | The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation |
| title_short | The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation |
| title_sort | novel role of kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid β plaques accumulation and tau protein hyperphosphorylation |
| topic | Alzheimer's disease Kallistatin Aβ42 BACE1 diabetes |
| url | https://elifesciences.org/articles/99462 |
| work_keys_str_mv | AT weiweiqi thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT yanlanlong thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT zimingli thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT zhenzhao thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT jinhuishi thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT wantingxie thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT laijianwang thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT yandantan thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT tizhou thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT mintingliang thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT pingjiang thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT binjiang thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT xiayang thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT guoquangao thenovelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT weiweiqi novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT yanlanlong novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT zimingli novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT zhenzhao novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT jinhuishi novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT wantingxie novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT laijianwang novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT yandantan novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT tizhou novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT mintingliang novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT pingjiang novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT binjiang novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT xiayang novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation AT guoquangao novelroleofkallistatininlinkingmetabolicsyndromesandcognitivememorydeteriorationbyinducingamyloidbplaquesaccumulationandtauproteinhyperphosphorylation |