Hye Joo Son, Seonok Kim, Seog-Young Kim, Jin Hwa Jung, Suk Hyun Lee, Soo-Jong Kim, Chanwoo Kim, Alice Hahn
{"title":"Three-Dimensional β-Amyloid Burden Correlation Between the Eye and Brain in Alzheimer's Disease Mice Using Light-Sheet Fluorescence Microscopy.","authors":"Hye Joo Son, Seonok Kim, Seog-Young Kim, Jin Hwa Jung, Suk Hyun Lee, Soo-Jong Kim, Chanwoo Kim, Alice Hahn","doi":"10.1167/iovs.66.3.34","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Recent studies have highlighted the significance of peripheral β-amyloid (Aβ) deposition, identifying the eye as a potential early detection site for Alzheimer's disease (AD). However, previous two-dimensional AD ocular studies have been unable to establish a clear correlation between the three-dimensional Aβ accumulation in the entire eyeball and brain while preserving structural integrity. This study employed a combined brain amyloid positron emission tomography/magnetic resonance (PET/MR) and light-sheet fluorescence microscopy (LSFM) platform to assess whether the three-dimensionally measured Aβ burden in the eyeball correlates with that in the brain.</p><p><strong>Methods: </strong>Thirteen eyeballs (6 AD, 7 control) and 17 brains (10 AD, 7 control) were collected from ten 44-week-old 5xFAD and seven control mice. The samples underwent tissue clearing and staining with thioflavin S (Aβ), anti-CD11b (microglia), and anti-ACSA-2 (astrocytes) for LSFM imaging and quantified via 3D surface volume. Standardized uptake value ratios from [18F]Flutemetamol PET/MR were also calculated.</p><p><strong>Results: </strong>AD eyeballs presented significantly greater plaque-like surface volumes (median, 51,091,002 µm³ [interquartile range, 38,488,272-64,869,828]) than controls (229,293 µm³ [115,863-311,5320]; P = 0.001). AD brains exhibited higher [18F]Flutemetamol uptake and greater plaque-like surface volumes (898,634,368 µm³ [556,263,488-1,105,326,720]) than controls (33,320,178 µm³ [26,842,538-62,716,956]; P < 0.001). A strong positive correlation was observed between the plaque-like surface volumes in the brain and that in the eyeball (r = 0.810, P = 0.001). No significant correlations were found in other morphologic parameters.</p><p><strong>Conclusions: </strong>Our observation of a strong correlation between the three-dimensional Aβ burden in the whole eyeball and brain advances our understanding of the systemic nature of Aβ pathology and suggests ocular Aβ as a potential independent predictor of brain Aβ burden.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"34"},"PeriodicalIF":5.0000,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932423/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Investigative ophthalmology & visual science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1167/iovs.66.3.34","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: Recent studies have highlighted the significance of peripheral β-amyloid (Aβ) deposition, identifying the eye as a potential early detection site for Alzheimer's disease (AD). However, previous two-dimensional AD ocular studies have been unable to establish a clear correlation between the three-dimensional Aβ accumulation in the entire eyeball and brain while preserving structural integrity. This study employed a combined brain amyloid positron emission tomography/magnetic resonance (PET/MR) and light-sheet fluorescence microscopy (LSFM) platform to assess whether the three-dimensionally measured Aβ burden in the eyeball correlates with that in the brain.
Methods: Thirteen eyeballs (6 AD, 7 control) and 17 brains (10 AD, 7 control) were collected from ten 44-week-old 5xFAD and seven control mice. The samples underwent tissue clearing and staining with thioflavin S (Aβ), anti-CD11b (microglia), and anti-ACSA-2 (astrocytes) for LSFM imaging and quantified via 3D surface volume. Standardized uptake value ratios from [18F]Flutemetamol PET/MR were also calculated.
Results: AD eyeballs presented significantly greater plaque-like surface volumes (median, 51,091,002 µm³ [interquartile range, 38,488,272-64,869,828]) than controls (229,293 µm³ [115,863-311,5320]; P = 0.001). AD brains exhibited higher [18F]Flutemetamol uptake and greater plaque-like surface volumes (898,634,368 µm³ [556,263,488-1,105,326,720]) than controls (33,320,178 µm³ [26,842,538-62,716,956]; P < 0.001). A strong positive correlation was observed between the plaque-like surface volumes in the brain and that in the eyeball (r = 0.810, P = 0.001). No significant correlations were found in other morphologic parameters.
Conclusions: Our observation of a strong correlation between the three-dimensional Aβ burden in the whole eyeball and brain advances our understanding of the systemic nature of Aβ pathology and suggests ocular Aβ as a potential independent predictor of brain Aβ burden.
期刊介绍:
Investigative Ophthalmology & Visual Science (IOVS), published as ready online, is a peer-reviewed academic journal of the Association for Research in Vision and Ophthalmology (ARVO). IOVS features original research, mostly pertaining to clinical and laboratory ophthalmology and vision research in general.