Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading
Abstract Depression has been widely recognized as an important accelerating factor contributing to the aggravation of cognitive decline in Alzheimer’s disease (AD) patients. Previous studies show that microglia-mediated neuroinflammation is a common and critical event in the etiology of both depress...
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| Format: | Article |
| Language: | English |
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BMC
2025-06-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03488-2 |
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| author | Xiaoli Liu Huijin Wang Xi Tian Yingqi Luo Minmin Ma Zilong Zheng Yaping Wang Shi Feng Qiushi Wang Zhuo Xu Wen Yao Siqiang Ren |
| author_facet | Xiaoli Liu Huijin Wang Xi Tian Yingqi Luo Minmin Ma Zilong Zheng Yaping Wang Shi Feng Qiushi Wang Zhuo Xu Wen Yao Siqiang Ren |
| author_sort | Xiaoli Liu |
| collection | DOAJ |
| description | Abstract Depression has been widely recognized as an important accelerating factor contributing to the aggravation of cognitive decline in Alzheimer’s disease (AD) patients. Previous studies show that microglia-mediated neuroinflammation is a common and critical event in the etiology of both depression and dementia, but whether and how microglia participate in the process of depression-exacerbating AD pathology is largely unknown. By establishing the learned helplessness depression model on 5×FAD mice, we confirmed that depression can indeed promote Aβ plaque deposition and deteriorate the cognitive performance of the AD mice. Importantly, we found that microglial lactate concentration is dramatically increased in the depressed AD brain, leading to activation of potassium channel Kv1.3 likely through non-direct-lactylation. The activated Kv1.3 further facilitates Aβ-containing exosome spreading from microglia in the vicinity of Aβ plaque into the surrounding brain tissue. Notably, conditional knock-out of Kv1.3 in microglia can reverse the depression-induced acceleration of AD pathology and cognitive decline. Together, our study highlights an important function of microglia Kv1.3 in the promotion of Aβ propagation in the context of depression-exacerbating AD pathology. |
| format | Article |
| id | doaj-art-e01a2d52777a46c18d3295474b38ea31 |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-e01a2d52777a46c18d3295474b38ea312025-08-20T03:27:11ZengBMCJournal of Neuroinflammation1742-20942025-06-0122112310.1186/s12974-025-03488-2Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreadingXiaoli Liu0Huijin Wang1Xi Tian2Yingqi Luo3Minmin Ma4Zilong Zheng5Yaping Wang6Shi Feng7Qiushi Wang8Zhuo Xu9Wen Yao10Siqiang Ren11Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityCenter for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical UniversityAbstract Depression has been widely recognized as an important accelerating factor contributing to the aggravation of cognitive decline in Alzheimer’s disease (AD) patients. Previous studies show that microglia-mediated neuroinflammation is a common and critical event in the etiology of both depression and dementia, but whether and how microglia participate in the process of depression-exacerbating AD pathology is largely unknown. By establishing the learned helplessness depression model on 5×FAD mice, we confirmed that depression can indeed promote Aβ plaque deposition and deteriorate the cognitive performance of the AD mice. Importantly, we found that microglial lactate concentration is dramatically increased in the depressed AD brain, leading to activation of potassium channel Kv1.3 likely through non-direct-lactylation. The activated Kv1.3 further facilitates Aβ-containing exosome spreading from microglia in the vicinity of Aβ plaque into the surrounding brain tissue. Notably, conditional knock-out of Kv1.3 in microglia can reverse the depression-induced acceleration of AD pathology and cognitive decline. Together, our study highlights an important function of microglia Kv1.3 in the promotion of Aβ propagation in the context of depression-exacerbating AD pathology.https://doi.org/10.1186/s12974-025-03488-2DepressionAlzheimer’s diseaseKv1.3LactateExosomesAβ spreading |
| spellingShingle | Xiaoli Liu Huijin Wang Xi Tian Yingqi Luo Minmin Ma Zilong Zheng Yaping Wang Shi Feng Qiushi Wang Zhuo Xu Wen Yao Siqiang Ren Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading Journal of Neuroinflammation Depression Alzheimer’s disease Kv1.3 Lactate Exosomes Aβ spreading |
| title | Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading |
| title_full | Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading |
| title_fullStr | Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading |
| title_full_unstemmed | Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading |
| title_short | Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading |
| title_sort | depression exacerbates ad pathology through lactate dependent activation of microglial kv1 3 to promote aβ containing exosome spreading |
| topic | Depression Alzheimer’s disease Kv1.3 Lactate Exosomes Aβ spreading |
| url | https://doi.org/10.1186/s12974-025-03488-2 |
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