Amyloid-β peptide signature associated with cerebral amyloid angiopathy in familial Alzheimer’s disease with APPdup and Down syndrome

Neurology Medical Laboratory Science Medicine Cell Biology Biochemistry Life Sciences Immunology
Alzheimer’s disease Down syndrome Aβ peptides cerebral amyloid angiopathy mass spectrometry neuropathology

Background Introduction

Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by the death of neurons in the brain. Its main pathological features include extracellular β-amyloid plaques and intracellular neurofibrillary tangles (NFTs). β-amyloid plaques are primarily composed of aggregated Amyloid beta peptides (Aβ). Additionally, Aβ peptides can also deposit in the walls of cerebral blood vessels, leading to cerebral amyloid angiopathy (CAA). Research has found that while Aβ plaques are common in the brains of AD patients, the degree of CAA varies among different patients. The authors of this paper mainly studied two rare and less-researched groups of patients: those with APP gene duplication (APPdup) and those with Down syndrome (DS). Compared to sporadic AD (SAD), these patients exhibited higher levels of Aβ deposition associated with CAA. This paper aims to compare the brain Aβ and Tau pathological features among different AD patient groups, particularly analyzing the spatial distribution of Aβ peptide sequences through mass spectrometry (MS) and MS imaging techniques.

Source of the Paper

This paper is co-authored by Amal Kasri, Elena Camporesi, Eleni Gkanatsiou, and others. The authors are affiliated with institutions including Pitié-Salpêtrière Hospital in Paris, Institute of Psychiatry at Kings College London Brain Bank (UK), Cambridge Brain Bank (UK), Queen Square Brain Bank (UK), and others. The article was submitted in February 2024, revised and accepted in June 2024, and published in the journal Acta Neuropathologica.

Research Process

Research Subjects

The study used postmortem brain materials from 51 cases from several brain banks in Europe. Samples included 15 control cases without clinical symptoms of AD (CTRL), 11 sporadic AD cases (SAD), 6 cases with APP point mutations (APP mutations), 7 APP gene duplication cases (APPdup), 4 Down syndrome cases without typical AD symptoms (DS), and 8 Down syndrome cases with AD symptoms (DS-AD).

Experimental Methods

  1. Tissue Processing and Immunohistochemical Analysis

    • Paraffin-embedded brain samples were used for immunohistochemical analysis. Staining was performed using specific monoclonal antibodies such as anti-Aβ antibody (6F/3D) and anti-Tau antibody (PS202/T205 Tau), combining automated and manual processing procedures.

  2. Mass Spectrometry Analysis

    • Mass spectrometry (MS) and MS imaging techniques were used to perform protein extraction and immunoprecipitation on the same set of frozen brain tissue samples, detecting and quantifying Aβ peptides. Samples were mainly analyzed based on soluble (TBS) and insoluble (FA) fractions.

  3. Statistical Analysis

    • Various statistical analysis methods such as one-way ANOVA, Tukey’s multiple comparison test, non-parametric Kruskal-Wallis test, and Spearman correlation analysis were utilized to analyze the experimental data.

Research Results

  1. Distribution of Aβ Deposition

    • Analyses of the prefrontal cortex revealed significant Aβ deposition in the blood vessels of APPdup and DS-AD patients, while in SAD and DS, Aβ deposition was mainly in the brain parenchyma. Notably, high levels of Aβ deposition were also found in the capillaries of APPdup patients.

  2. Tau Pathological Features

    • Tau protein analysis showed significant Tau deposition in all AD-related samples, whereas less Tau deposition was observed in the Down syndrome group (DS). DS-AD and patients with APP mutations exhibited high levels of Tau protein deposition, including neurofibrillary tangles and glial fibrillary tangles.

  3. Mass Spectrometry Results

    • MALDI-MS analysis showed high levels of Aβ1-37, Aβ1-38, Aβ1-39, and Aβ1-40 in the cortex and hippocampus of APPdup and DS-AD groups, whereas Aβ1-42 was predominant in SAD patients. Further LC-MS quantitative analysis confirmed significant increases in these peptides in APPdup and DS-AD patients, identifying associations with CAA.

Research Conclusion

The study indicates that Aβ overexpression caused by APP gene duplication is a strong genetic factor leading to CAA. The specific Aβ peptide patterns observed in APPdup samples suggest selective deposition in the vascular walls. Additionally, the study found that DS patients might have protective mechanisms preventing Aβ peptide deposition in blood vessels, thereby reducing CAA-related complications.

Research Highlights

  1. Identification of Specific Aβ Peptide Patterns

    • Through mass spectrometry, the study detailed the unique Aβ peptide deposition patterns in the brains of APPdup patients, including Aβ1-37, Aβ1-38, Aβ1-39, and Aβ1-40.

  2. Protective Mechanisms in DS Patients

    • The study pointed out that Down syndrome patients might have protective mechanisms that prevent Aβ peptide deposition in the vascular walls, reducing CAA-related complications.

  3. Combined Pathology and Mass Spectrometry Analysis Methods

    • By combining immunohistochemistry with mass spectrometry imaging techniques, the research obtained more detailed and accurate Aβ peptide distribution data, deepening the understanding of the relationship between CAA and AD.

Research Significance

This study, through meticulous experiments and data analyses, revealed the pathological mechanisms and distribution characteristics of Aβ peptides in AD and CAA under genetic backgrounds. This provides new directions and potential biomarkers for future AD and CAA diagnosis and treatment research. Furthermore, the proposed protective mechanisms in DS patients offer new insights for AD treatment strategies, suggesting including DS patients in anti-Aβ immunotherapy clinical trials.

Conclusion

This research, through several innovative and detailed experimental methods, uncovered the differences and patterns in Aβ deposition among AD and CAA patients, as well as the mechanisms of these depositions under different genetic backgrounds. These findings provide valuable scientific evidence for future studies and treatment of AD and CAA.

The study not only delves into the pathological mechanisms of AD and CAA but also explores potential biomarkers and treatment strategies for the future. Such research will continue to advance our understanding of neurodegenerative diseases and potentially lead to the development of more effective diagnostic and therapeutic methods.