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 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.

• author: Andersson, Emelie ; Schultz, Nina ; Saito, Takashi ; Saido, Takaomi C. ; Blennow, Kaj ; Gouras, Gunnar K. ; Zetterberg, Henrik and Hansson, Oskar
• organization: Neuroinflammation (research group); MultiPark: Multidisciplinary research focused on Parkinson´s disease; Clinical Memory Research (research group); National Graduate School on Ageing and Health (research group); Experimental Dementia Research (research group); LU Profile Area: Proactive Ageing; Lund University Bioimaging Center
• publishing date: 2023-12
• type: Contribution to journal
• publication status: published
• subject: Neurosciences
• keywords: Alzheimer’s disease, Beta-amyloid, Biomarker, Blood, Cerebrospinal fluid
• in: Alzheimer's Research and Therapy
• volume: 15
• issue: 1
• article number: 64
• publisher: BioMed Central (BMC)
• external identifiers: pmid:36964585; scopus:85150988544
• ISSN: 1758-9193
• DOI: 10.1186/s13195-023-01196-8
• language: English
• LU publication?: yes
• additional info: Funding Information: Open access funding provided by Lund University. Work at Lund University was supported by the Swedish Research Council (2016–00906), the Knut and Alice Wallenberg foundation (2017–0383), the Marianne and Marcus Wallenberg foundation (2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation (AF-939932), the Swedish Brain Foundation (FO2021-0293), The Parkinson foundation of Sweden (1280/20), the Cure Alzheimer’s fund, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2020–0314), and the Swedish federal government under the ALF agreement (2018-Projekt0279). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532); the European Union’s Horizon Europe research and innovation programme under grant agreement no. 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320); the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809–2016862); the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21–831376-C, #ADSF-21–831381-C, and #ADSF-21–831377-C); the Bluefield Project; the Olav Thon Foundation; the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270); the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 860197 (MIRIADE); the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694); and the UK Dementia Research Institute at UCL (UKDRI-1003). KB is supported by the Swedish Research Council (#2017–00915 and #2022–00732); the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809–2016615); the Swedish Alzheimer Foundation (#AF-930351, #AF-939721 and #AF-968270); Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006); the Swedish state under the agreement between the Swedish government and the County Councils; the ALF agreement (#ALFGBG-715986 and #ALFGBG-965240); the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466–236); the National Institute of Health (NIH), USA (grant #1R01AG068398-01); the Alzheimer’s Association 2021 Zenith Award (ZEN-21–848495); and the Alzheimer’s Association 2022–2025 Grant (SG-23–1038904 QC). Publisher Copyright: © 2023, The Author(s).
• id: 6b9ea21d-011a-431b-af3a-60475c0608a6
• date added to LUP: 2023-04-18 17:04:34
• date last changed: 2024-09-08 09:08:37