Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App NL−F/NL−F knock-in mouse model of Alzheimer’s disease
Abstract Background Aβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer’s disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate...
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-023-01196-8 |
| _version_ | 1797860003959275520 |
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| author | Emelie Andersson Nina Schultz Takashi Saito Takaomi C. Saido Kaj Blennow Gunnar K. Gouras Henrik Zetterberg Oskar Hansson |
| author_facet | Emelie Andersson Nina Schultz Takashi Saito Takaomi C. Saido Kaj Blennow Gunnar K. Gouras Henrik Zetterberg Oskar Hansson |
| author_sort | Emelie Andersson |
| collection | DOAJ |
| description | Abstract Background Aβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer’s disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD. Methods CSF, serum, and brain tissue were collected from 3- to 18-month-old App NL−F/NL−F knock-in mice (n = 48) and 2–18-month-old App NL/NL knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay. Results In App NL−F/NL−F knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in App NL/NL knock-in mice during the observation time. Conclusions Our findings suggest a temporal sequence of events in App NL−F/NL−F knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum. |
| first_indexed | 2024-04-09T21:38:43Z |
| format | Article |
| id | doaj.art-2583dc4d799c47f49b216a7fc4f14f50 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-04-09T21:38:43Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-2583dc4d799c47f49b216a7fc4f14f502023-03-26T11:07:37ZengBMCAlzheimer’s Research & Therapy1758-91932023-03-0115111310.1186/s13195-023-01196-8Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App NL−F/NL−F knock-in mouse model of Alzheimer’s diseaseEmelie Andersson0Nina Schultz1Takashi Saito2Takaomi C. Saido3Kaj Blennow4Gunnar K. Gouras5Henrik Zetterberg6Oskar Hansson7Clinical Memory Research Unit, Lund UniversityClinical Memory Research Unit, Lund UniversityDepartment of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical SciencesLaboratory for Proteolytic Neuroscience, RIKEN Brain Science InstituteDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of GothenburgDepartment of Experimental Medical Science, Experimental Dementia Research Unit, Lund UniversityDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of GothenburgClinical Memory Research Unit, Lund UniversityAbstract Background Aβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer’s disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD. Methods CSF, serum, and brain tissue were collected from 3- to 18-month-old App NL−F/NL−F knock-in mice (n = 48) and 2–18-month-old App NL/NL knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay. Results In App NL−F/NL−F knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in App NL/NL knock-in mice during the observation time. Conclusions Our findings suggest a temporal sequence of events in App NL−F/NL−F knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum.https://doi.org/10.1186/s13195-023-01196-8Alzheimer’s diseaseBiomarkerCerebrospinal fluidBloodBeta-amyloid |
| spellingShingle | Emelie Andersson Nina Schultz Takashi Saito Takaomi C. Saido Kaj Blennow Gunnar K. Gouras Henrik Zetterberg Oskar Hansson Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App NL−F/NL−F knock-in mouse model of Alzheimer’s disease Alzheimer’s Research & Therapy Alzheimer’s disease Biomarker Cerebrospinal fluid Blood Beta-amyloid |
| title | Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App NL−F/NL−F knock-in mouse model of Alzheimer’s disease |
| title_full | Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App NL−F/NL−F knock-in mouse model of Alzheimer’s disease |
| title_fullStr | Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App NL−F/NL−F knock-in mouse model of Alzheimer’s disease |
| title_full_unstemmed | Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App NL−F/NL−F knock-in mouse model of Alzheimer’s disease |
| title_short | Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App NL−F/NL−F knock-in mouse model of Alzheimer’s disease |
| title_sort | cerebral aβ deposition precedes reduced cerebrospinal fluid and serum aβ42 aβ40 ratios in the app nl f nl f knock in mouse model of alzheimer s disease |
| topic | Alzheimer’s disease Biomarker Cerebrospinal fluid Blood Beta-amyloid |
| url | https://doi.org/10.1186/s13195-023-01196-8 |
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