Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia

Zhu, Xiaoyue; Schrader, Joseph M.; Irizarry, Brandon A.; Smith, Steven O.; Nostrand, William E. Van

doi:10.3390/biomedicines10112982

Cited by 6 publications

(4 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ITC experiments we have performed in this work point to this being a selective and saturable interaction that is energy requiring and hence possibly deliberate and important for cellular physiology and/or pathology. Aβ peptide binding to EVs detected using ITC unveiled that, while Aβ40 binding was endothermic and saturable, the more aggregation prone Aβ42 [83][84][85], was peptide-form dependent, with endothermic heat exchanges more robustly observed when preformed fibrillar Aβ42 (Aβ42F) was added to the assay. Thus, our ITC experiments suggest a preference for binding to fibrillar vs. monomeric forms of Aβ42.…”

Section: Discussionmentioning

confidence: 99%

Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles

Coughlan,

Lindenberger,

Jacot

et al. 2024

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the fifth leading cause of death among adults aged 65 and older, yet the onset and progression of the disease is poorly understood. What is known is that the presence of amyloid, particularly polymerized Aβ42, defines when people are on the AD continuum. Interestingly, as AD progresses, less Aβ42 is detectable in the plasma, a phenomenon thought to result from Aβ becoming more aggregated in the brain and less Aβ42 and Aβ40 being transported from the brain to the plasma via the CSF. We propose that extracellular vesicles (EVs) play a role in this transport. EVs are found in bodily fluids such as blood, urine, and cerebrospinal fluid and carry diverse “cargos” of bioactive molecules (e.g., proteins, nucleic acids, lipids, metabolites) that dynamically reflect changes in the cells from which they are secreted. While Aβ42 and Aβ40 have been reported to be present in EVs, it is not known whether this interaction is specific for these peptides and thus whether amyloid-carrying EVs play a role in AD and/or serve as brain-specific biomarkers of the AD process. To determine if there is a specific interaction between Aβ and EVs, we used isothermal titration calorimetry (ITC) and discovered that Aβ42 and Aβ40 bind to EVs in manner that is sequence specific, saturable, and endothermic. In addition, Aβ incubation with EVs overnight yielded larger amounts of bound Aβ peptide that was fibrillar in structure. These findings point to a specific amyloid–EV interaction, a potential role for EVs in the transport of amyloid from the brain to the blood, and a role for this amyloid pool in the AD process.

show abstract

Section: Discussionmentioning

confidence: 99%

Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles

Coughlan,

Lindenberger,

Jacot

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

“…Individuals with brain amyloidosis and normal cognition exhibited higher levels of CSF Aβ42 than did those with MCI or AD, suggesting that higher levels of CSF Aβ42 were associated with preserved cognitive function in individuals with brain amyloidosis [203]. Microglia treated with Aβ42 fibrils exhibited upregulated gene expression compared to those treated with Aβ40 fibrils.…”

Section: Aβ42/40mentioning

confidence: 97%

Biomarkers in neurodegenerative diseases: a broad overview

Selvam,

Ayyavoo

2024

Explor Neuroprot Ther

View full text Add to dashboard Cite

Degeneration and dysfunction of neurons in the brain are hallmarks of neurodegenerative diseases. Over the past decades, significant efforts have been devoted to the development and validation of biomarkers for neurodegenerative diseases. The range and diversity of biomarkers for central nervous system (CNS) diseases has continued to expand, encompassing biofluid-based sources such as blood or cerebrospinal fluid (CSF), nucleic acids, tissues, and imaging. While imaging and tissue biopsy-based markers are continually being identified and their applications expanding, they do have limitations compared with RNA and protein biomarkers. This review comprehensively summarizes various biomarkers, including microRNA (miRNA), long noncoding RNA (lncRNA), circulating miRNA (cimiRNA), and proteins, in the context of CNS disorders. In addition, the review emphasizes the existing limitations and challenges associated with the use of biomarkers in both clinical practice and research on neurodegenerative diseases. In conclusion, this review provides an insightful overview of the identified biomarkers for neurodegenerative diseases, underscoring the crucial role of biomarker research in combating these debilitating conditions. The article also highlights future challenges related to the implementation of novel biomarkers in clinical practice and trials, thereby contributing to the ongoing efforts to advance the understanding and management of neurodegenerative diseases.

show abstract

“…The study reported different toxic effect of polymorphic Aβ fibril morphologies on primary rat embryonic hippocampal neurons with Aβ fibrils grown under quiescent conditions having higher toxicity than those grown under agitated conditions (Petkova et al, 2005 ). At the in vivo level, studies showed differential neuropathological effects in transgenic mouse models injected with distinct polymorphic Aβ fibrils, including Aβ fibrils extracted from familial and sporadic AD cases, as well as synthetically produced Aβ fibrils with distinct C‐terminal variants (Ruiz‐Riquelme et al, 2021 ; Stöhr et al, 2014 ; Watts et al, 2014 ; Zhu et al, 2022 ). Synthetic Aβ fibrils injected into mice have been shown to be less potent in inducing Aβ deposition compared with brain‐derived fibrils (Stöhr et al, 2012 ).…”

Section: Structural Polymorphism Of Synthetic and Brain‐derived ...mentioning

confidence: 99%

Structural polymorphism and cytotoxicity of brain‐derived β‐amyloid extracts

Adem

Lee

2023

Protein Science

View full text Add to dashboard Cite

To date, more than 37 amyloidogenic proteins have been found to form toxic aggregates that are implicated in the progression of numerous debilitating protein misfolding diseases including Alzheimer's disease (AD). Extensive literature highlights the role of β‐amyloid (Aβ) aggregates in causing excessive neuronal cell loss in the brains of AD patients. In fact, major advances in our understanding of Aβ aggregation process, including kinetics, toxicity, and structures of fibrillar aggregates have been revealed by examining in vitro preparations of synthetic Aβ peptides. However, ongoing research shows that brain‐derived Aβ aggregates have specific characteristics that distinguish them from in vitro prepared species. Notably, the molecular structures of amyloid fibrils grown in the human brain were found to be markedly different than synthetic Aβ fibrils. In addition, recent findings report the existence of heterogeneous Aβ proteoforms in AD brain tissue in contrast to synthetically produced full‐length aggregates. Despite their high relevance to AD progression, brain‐derived Aβ species are less well‐characterized compared with synthetic aggregates. The aim of this review is to provide an overview of the literature on brain‐derived Aβ aggregates with particular focus on recent studies that report their structures as well as pathological roles in AD progression. The main motivation of this review is to highlight the importance of utilizing brain‐derived amyloids for characterizing the structural and toxic effects of amyloid species. With this knowledge, brain‐derived aggregates can be adopted to identify more relevant drug targets and validate potent aggregation inhibitors toward designing highly effective therapeutic strategies against AD.

show abstract

Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia

Cited by 6 publications

References 109 publications

Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles

Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles

Biomarkers in neurodegenerative diseases: a broad overview

Structural polymorphism and cytotoxicity of brain‐derived β‐amyloid extracts

Contact Info

Product

Resources

About