CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice
The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dend...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996123000712 |
| _version_ | 1797867429456510976 |
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| author | Griffin A. Greco Mitchell Rock Matthew Amontree Maria Fe Lanfranco Holly Korthas Sung Hyeok Hong R. Scott Turner G. William Rebeck Katherine Conant |
| author_facet | Griffin A. Greco Mitchell Rock Matthew Amontree Maria Fe Lanfranco Holly Korthas Sung Hyeok Hong R. Scott Turner G. William Rebeck Katherine Conant |
| author_sort | Griffin A. Greco |
| collection | DOAJ |
| description | The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power, a neuronal population activity which is important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power, while attenuation of ECM can instead enhance this endpoint. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice. Importantly, as compared to APOE4/wild-type heterozygotes, APOE4/CCR5 knockout heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals. |
| first_indexed | 2024-04-09T23:41:08Z |
| format | Article |
| id | doaj.art-fd4b70330d404358b61b5d8721a3fd22 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-09T23:41:08Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-fd4b70330d404358b61b5d8721a3fd222023-03-19T04:37:10ZengElsevierNeurobiology of Disease1095-953X2023-04-01179106057CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement miceGriffin A. Greco0Mitchell Rock1Matthew Amontree2Maria Fe Lanfranco3Holly Korthas4Sung Hyeok Hong5R. Scott Turner6G. William Rebeck7Katherine Conant8Georgetown University School of Medicine (GUMC), Department of Pharmacology, United States of AmericaGUMC, United States of AmericaGUMC, United States of America; Interdisciplinary Program in Neuroscience, United States of AmericaGUMC, Department of Neuroscience, United States of AmericaInterdisciplinary Program in Neuroscience, United States of AmericaGUMC, Department of Biochemistry and Molecular & Cellular Biology, United States of AmericaGUMC, Department of Neurology, United States of AmericaInterdisciplinary Program in Neuroscience, United States of America; GUMC, Department of Neuroscience, United States of AmericaInterdisciplinary Program in Neuroscience, United States of America; GUMC, Department of Neuroscience, United States of America; Corresponding author at: Interdisciplinary Program in Neuroscience, United States of AmericaThe APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power, a neuronal population activity which is important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power, while attenuation of ECM can instead enhance this endpoint. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice. Importantly, as compared to APOE4/wild-type heterozygotes, APOE4/CCR5 knockout heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.http://www.sciencedirect.com/science/article/pii/S0969996123000712Extracellular matrixCCR5APOEMMPTIMP-1 |
| spellingShingle | Griffin A. Greco Mitchell Rock Matthew Amontree Maria Fe Lanfranco Holly Korthas Sung Hyeok Hong R. Scott Turner G. William Rebeck Katherine Conant CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice Neurobiology of Disease Extracellular matrix CCR5 APOE MMP TIMP-1 |
| title | CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice |
| title_full | CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice |
| title_fullStr | CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice |
| title_full_unstemmed | CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice |
| title_short | CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice |
| title_sort | ccr5 deficiency normalizes timp levels working memory and gamma oscillation power in apoe4 targeted replacement mice |
| topic | Extracellular matrix CCR5 APOE MMP TIMP-1 |
| url | http://www.sciencedirect.com/science/article/pii/S0969996123000712 |
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