Retinal arterial Aβ40 deposition is linked with tight junction loss and cerebral amyloid angiopathy in MCI and AD patients

Haoshen Shi; Yosef Koronyo; Dieu-Trang Fuchs; Julia Sheyn; Ousman Jallow; Krishna Mandalia; Stuart L Graham; Vivek K Gupta; Mehdi Mirzaei; Andrei A Kramerov; Alexander V Ljubimov; Debra Hawes; Carol A Miller; Keith L Black; Roxana O Carare; Maya Koronyo-Hamaoui

doi:10.1002/alz.13086

Retinal arterial Aβ₄₀ deposition is linked with tight junction loss and cerebral amyloid angiopathy in MCI and AD patients

Alzheimers Dement. 2023 Nov;19(11):5185-5197. doi: 10.1002/alz.13086. Epub 2023 May 11.

Authors

Haoshen Shi¹, Yosef Koronyo¹, Dieu-Trang Fuchs¹, Julia Sheyn¹, Ousman Jallow¹, Krishna Mandalia¹, Stuart L Graham², Vivek K Gupta², Mehdi Mirzaei², Andrei A Kramerov³, Alexander V Ljubimov^{1

3

4}, Debra Hawes⁵, Carol A Miller⁵, Keith L Black¹, Roxana O Carare⁶, Maya Koronyo-Hamaoui^{1

4

7}

Affiliations

¹ Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
² Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
³ Department of Biomedical Sciences and Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁴ Department of Biomedical Sciences, Division of Applied Cell Biology and Physiology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁵ Department of Pathology Program in Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁶ Department of Clinical Neuroanatomy, University of Southampton, Southampton, UK.
⁷ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Abstract

Introduction: Vascular amyloid beta (Aβ) protein deposits were detected in retinas of mild cognitively impaired (MCI) and Alzheimer's disease (AD) patients. We tested the hypothesis that the retinal vascular tight junctions (TJs) were compromised and linked to disease status.

Methods: TJ components and Aβ expression in capillaries and larger blood vessels were determined in post mortem retinas from 34 MCI or AD patients and 27 cognitively normal controls and correlated with neuropathology.

Results: Severe decreases in retinal vascular zonula occludens-1 (ZO-1) and claudin-5 correlating with abundant arteriolar Aβ₄₀ deposition were identified in MCI and AD patients. Retinal claudin-5 deficiency was closely associated with cerebral amyloid angiopathy, whereas ZO-1 defects correlated with cerebral pathology and cognitive deficits.

Discussion: We uncovered deficiencies in blood-retinal barrier markers for potential retinal imaging targets of AD screening and monitoring. Intense retinal arteriolar Aβ₄₀ deposition suggests a common pathogenic mechanism of failed Aβ clearance via intramural periarterial drainage.

Keywords: Alzheimer's disease; amyloid angiopathy; blood-retinal barrier; retinopathy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / pathology
Amyloid beta-Peptides / metabolism
Cerebral Amyloid Angiopathy* / pathology
Claudin-5 / metabolism
Cognitive Dysfunction / metabolism
Cognitive Dysfunction / pathology
Humans
Retina* / pathology
Tight Junctions / metabolism
Tight Junctions / pathology

Substances

Amyloid beta-Peptides
Claudin-5

Abstract

Publication types

MeSH terms

Substances

Grants and funding