AI Article Synopsis
Article Abstract
Identifying the systems-level mechanisms that lead to Alzheimer's disease, an unmet need, is an essential step toward the development of therapeutics. In this work, we report that the key disease-causative mechanisms, including dedifferentiation and repression of neuronal identity, are triggered by changes in chromatin topology. Here, we generated human induced pluripotent stem cell (hiPSC)-derived neurons from donor patients with early-onset familial Alzheimer's disease (EOFAD) and used a multiomics approach to mechanistically characterize the modulation of disease-associated gene regulatory programs. We demonstrate that EOFAD neurons dedifferentiate to a precursor-like state with signatures of ectoderm and nonectoderm lineages. RNA-seq, ATAC-seq, and ChIP-seq analysis reveals that transcriptional alterations in the cellular state are orchestrated by changes in histone methylation and chromatin topology. Furthermore, we demonstrate that these mechanisms are observed in EOFAD-patient brains, validating our hiPSC-derived neuron models. The mechanistic endotypes of Alzheimer's disease uncovered here offer key insights for therapeutic interventions.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673760 | PMC |
| http://dx.doi.org/10.1126/sciadv.aba5933 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Synaptic dysfunction is one of the earliest cellular defects observed in Alzheimer's disease (AD) and Parkinson's disease (PD), occurring before widespread protein aggregation, neuronal loss, and cognitive decline. While the field has focused on the aggregation of Tau and α-Synuclein (α-Syn), emerging evidence suggests that these proteins may drive presynaptic pathology even before their aggregation. Therefore, understanding the mechanisms by which Tau and α-Syn affect presynaptic terminals offers an opportunity for developing innovative therapeutics aimed at preserving synapses and potentially halting neurodegeneration.
View Article and Find Full Text PDFUltrasensitive Protein Aggregate Quantification Assays for Neurodegenerative Diseases on the Simoa Platform.
Anal Chem
December 2024
Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
Nanoscale aggregates play a key role in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. However, quantifying these aggregates in complex biological samples, such as biofluids and postmortem brain tissue, has been challenging due to their low concentration and small size, necessitating the development of methods with high sensitivity and specificity. Here, we have developed ultrasensitive assays utilizing the Quanterix Simoa platform to detect α-synuclein, β-amyloid and tau aggregates, including those with common posttranslational modifications such as truncation of α-synuclein and AT8 phosphorylation of tau aggregates.
View Article and Find Full Text PDFPrecision diagnosis of cognitive impairment due to Alzheimer's disease for therapeutic interventions.
Alzheimers Dement
December 2024
Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
With the advent of anti-amyloid monoclonal antibody (AAMA) therapy, precision diagnosis is necessary for identifying appropriate patients with cognitive disorders due to Alzheimer's disease. Therapy with AAMAs requires that candidates be diagnosed with mild cognitive impairment or mild dementia, have elevated brain amyloid-β, have good physical, psychiatric, and medical health, and lack clinical or biomarker evidence of potentially impactful non-Alzheimer brain disorders. The first three diagnostic activities are the core of the Clinical Practice Guidelines, but the last element of the precision diagnosis requires new decision-making tools for recognizing multi-etiology cognitive impairment.
View Article and Find Full Text PDFNext generation brain health: transforming global research and public health to promote prevention of dementia and reduce its risk in young adult populations.
Lancet Healthy Longev
December 2024
Global Brain Health Institute (GBHI), Trinity College Dublin, Dublin, Ireland; Centre for Dementia Research, School of Health, Leeds Beckett University, Leeds, UK.
Efforts to prevent dementia can benefit from precision interventions delivered to the right population at the right time; that is, when the potential to reduce risk is the highest. Young adults (aged 18-39 years) are a neglected population in dementia research and policy making despite being highly exposed to several known modifiable risk factors. The risk and protective factors that have the biggest effect on dementia outcomes in young adulthood, and how these associations differ across regions and groups, still remain unclear.
View Article and Find Full Text PDFBrain region and sex-dependent heterogeneity of PUFA/oxylipin profile, microglia morphology and their relationship.
Prostaglandins Leukot Essent Fatty Acids
December 2024
Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, , Netherlands. Electronic address:
Lipid dyshomeostasis and neuroinflammation are key hallmarks of neuropsychiatric and neurodegenerative disorders, including major depressive disorder and Alzheimer's disease. In particular, polyunsaturated fatty acids (PUFAs) and their derivatives called oxylipins gained specific interest in this context, especially considering their capacity to orchestrate neuroinflammatory responses via direct modulation of microglia. The hippocampus and hypothalamus are crucial brain regions for regulating mood and cognition that are implicated in a variety of neuropsychiatric and neurodegenerative disorders and there is ample evidence for the sex-bias in risks for the development as well as sex-bias in the presentation of such psychiatric diseases, including the neuroinflammatory response.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!