Research Report on Abnormal Tau Proteins in the Retina of Alzheimer’s Disease Patients

Introduction

Alzheimer’s disease (AD) is the primary cause of dementia in the elderly population worldwide. The pathological features of AD include the deposition of amyloid beta-protein (Aβ) and the aggregation of abnormal microtubule-associated tau proteins in the brain. During the progression of AD, tau proteins undergo post-translational modifications such as hyperphosphorylation (p-tau) and citrullination (cit-tau), forming toxic oligomers (oligomeric-tau, oligo-tau). These oligomers can propagate in infected neurons, leading to the aggregation of tau proteins into fibrils and paired helical filaments (PHF), ultimately forming neurofibrillary tangles (NFTs), impairing neuronal function, and causing cell death.

The tau pathology in the brain typically occurs after Aβ pathology, which starts accumulating decades before the onset of clinical symptoms. This offers a potential window for early intervention. Hence, developing viable, economical, and minimally invasive technologies for the early screening and monitoring of AD is crucial.

The retina is the only part of the central nervous system (CNS) not encased in bone, and its accessibility and high-resolution imaging capabilities make it a potential tool for AD screening. This study aims to explore various forms of tau protein abnormalities in the retina and their connection to AD.

Source

This study was authored by Haoshen Shi, Nazanin Mirzaei, Yosef Koronyo, among others, primarily from the University of Southern California (USC). The research was published in the 2024 issue of the journal Acta Neuropathologica.

Research Process

Source and Handling of Samples: The study collected ocular and brain tissues from 75 donors, including 34 AD patients, 11 mild cognitive impairment (MCI) patients, and 30 normal cognition (NC) controls. Additionally, there were 4 non-AD dementia (D-NAD) patients. These tissues were primarily obtained from the Alzheimer’s Disease Research Center (ADRC) of USC and the National Disease Research Interchange (NDRI). All tissue samples underwent standard procedures for fixation, preservation, and processing.

Pathological and Clinical Assessment: The severity of brain diseases was semi-quantitatively assessed, including pathological features such as Aβ plaques, NFTs, neurofibrils (NTs), and brain atrophy. Clinical cognitive status was evaluated using the Clinical Dementia Rating (CDR) and Mini Mental State Examination (MMSE).

Immunohistochemistry and Imaging Techniques: To investigate different forms of tau proteins, immunohistochemistry (IHC) and NanoString GeoMx Digital Spatial Profiling (DSP) were performed on retinal and brain tissues. IHC utilized various specific antibodies, such as at8, ps396, citr209, oligo-tau, to label and analyze different tau conformations.

Research Results

Spatial Distribution and Disease Association of Tau Pathology: 1. MC-1 Positive Tau Tangles: IHC detection revealed a significant increase of MC-1 positive tau tangles in the AD retina, primarily located in the ganglion cell layer (GCL) and inner nuclear layer (INL), indicating pathological structures in the AD retina similar to NFTs in the brain.

1. Oligomeric-Tau (Oligo-tau): T22 antibody marking showed a substantial increase of oligomeric tau in the retinas of AD and MCI patients, especially in the outer plexiform layer (OPL) and inner plexiform layer (IPL). These oligomeric tau correlates significantly with NFT burden in the brain.

2. Phosphorylated Tau (p-tau): GeoMx DSP analysis revealed a significant increase of various p-tau forms (such as ps214, ps396, ps404) in the retinas and corresponding brain tissues of AD and MCI patients. These forms of p-tau are also significantly associated with brain pathology and cognitive status.

3. Citrullinated Tau (cit-tau): The study found a marked increase of cit209-tau in the retinas of AD and MCI patients, closely associated with an increase in ps202/t205 phosphorylated tau (at8 positive). The increase of citrullinated tau was particularly significant in the central retina and correlated with cognitive assessment scores such as CDR and MMSE.

Combination Associations of Different Tau Protein Forms: Pearson correlation analysis showed a strong positive correlation between retinal oligo-tau and Aβ42 forms and arterial Aβ40 burden, while cit-tau also showed a significant correlation with Aβ42 burden.

Conclusion and Value

In conclusion, this study is the first to reveal various forms of tau protein abnormalities in the retinas of AD and MCI patients, especially oligomeric and citrullinated tau proteins. These protein abnormalities are significantly associated with corresponding brain pathology and cognitive status. The findings suggest that specific forms of retinal tau proteins could serve as biomarkers for future early AD detection and disease progression evaluation. This discovery provides a new theoretical foundation and potential application value for developing non-invasive retinal imaging technologies for AD screening.

Research Highlights

1. Newly Discovered Retinal Tau Protein Forms: The study is the first to discover oligomeric tau and citrullinated tau in the AD retina, filling a research gap in this field.
2. Comprehensive Exploration of Various Pathological Forms: Combining GeoMx Digital Spatial Profiling and immunohistochemistry technologies, the study systematically analyzed various retinal tau protein forms and their relationships with AD progression.
3. Potential for Non-Invasive Detection: The study supports the use of retinal imaging-based early AD screening, showcasing significant clinical translational potential.