Inner blood-retinal barrier alterations associated with vascular amyloidosis in MCI and AD patients

Background: Blood-brain barrier (BBB) breakdown in Alzheimer’s disease (AD) is linked to cerebral amyloid-beta (Aβ) accumulation and cognitive decline. Previously, we identified substantial retinal pericyte loss along with vascular amyloidosis in mild cognitively impaired (MCI) and AD patients. In double transgenic APP_SWE/PS1_∆E9 (ADtg) mice, we further demonstrated substantial retinal capillary degeneration and microvascular leakage in comparison to wild type (WT) mice. Here, we sought to expand our investigation of inner blood-retinal barrier (iBRB) integrity in relation to retinal and cerebral pathological benchmarks in MCI and AD patients compared to cognitively normal (CN) controls. Method: Postmortem human eyes and brains were obtained from USC-ADRC. Retinas were isolated from 35 AD patients, 15 MCI patients, and 20 age- and sex-matched healthy controls. Retinal cross sections spanning along ora serrata to optic disc were prepared from four pre-defined quadrants: superiortemporal, temporalinferior, inferiornasal, and nasalsuperior. Histological examination was performed by immunostaining for different Aβ alloforms, tight junctions (zonula occulden-1, claudin-1 and -5), and blood vessels (lectin). Retinal microvessels were isolated for evaluating capillary degeneration. Stereological quantifications were performed and then correlated with the respective neuropathological reports of these patients. Mass spectrometry analysis of proteins isolated from another AD and control patients’ cohort was conducted to validate our data. Result: Our preliminary results showed early and significant downregulation of zonula occulden-1 in retinal blood vessels of MCI and AD patients compared to controls. Downregulation of this key tight junction molecule was associated with increased retinal vascular Aβ accumulation. In addition, significant deficiencies of vascular-related proteins including smoothelin, vascular endothelial zinc finger 1 (VEZF1), catenin isoform 1 were detected in retinal homogenates from AD patients versus controls by global proteome analysis. Analysis of isolated retinal blood vessels revealed capillary degeneration along with Alzheimer’s-relevant vascular pathology in these patients. Conclusion: Our data suggested an early alteration of iBRB integrity that contributed to Aβ accumulation in retinal blood vessels, consistent with previous reports in BBB of AD patients. Our results provide new insights into AD-related vascular pathomechanisms in the retina that can be further evaluated for retinal imaging.