Regional susceptibility of PV interneurons in an hAPP-KI mouse model of Alzheimer’s disease pathology DOI Creative Commons
Mercedes M. Gonzalez, Benjamin Magondu, Matthew JM Rowan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Early-stage Alzheimer's pathology correlates with disrupted neuronal excitability, which can drive network and cognitive dysfunction even prior to neurodegeneration. However, the emergence extent of these changes may vary by brain region cell types situated in those regions. Here we aimed investigate effects AD on different neuron subtypes both entorhinal cortex, a enhanced early AD, primary visual relatively unaffected early-stage AD. We designed employed semi-automated patch clamp electrophysiology apparatus record from fast-spiking parvalbumin interneurons excitatory neurons regions, recording over 150 cells young adult APP-KI mice. In amyloid overproduction resulted PV interneuron hypoexcitability, whereas were concurrently hyperexcitable. Conversely, either subclass largely cortex. Together, findings suggest that but not play an integral role progression.

Language: Английский

Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia DOI
Jorge J. Llibre‐Guerra, María Victoria Fernández, Nelly Joseph‐Mathurin

et al.

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Language: Английский

Citations

3
Sex-specific Associations of Gene Expression with Alzheimer's Disease Neuropathology and Ante-mortem Cognitive Performance DOI Creative Commons
Mabel Seto,

Michelle Clifton,

Manuel J. Gómez

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract The biological mechanisms underlying women’s increased Alzheimer’s disease (AD) prevalence remain undefined. Previous case/control studies have identified sex-biased molecular pathways, but sex-specific relationships between gene expression and AD endophenotypes, particularly sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated associations post-mortem β-amyloid tau as well antemortem longitudinal cognition. Of 23,118 significant associations, 10% were in one not the other (sex-specific). Most females (73%) associated with tangles cognition (90%). Four X-linked genes, MCF2 , HDAC8 FTX SLC10A3 demonstrated differences their endophenotypes (i.e., x interaction). Our results also uncovered including a female-specific role of neuroinflammation neuronal development, reinforcing potential for sex-aware analyses to enhance precision medicine approaches AD.

Language: Английский

Citations

1
CRISPRi-based screens in iAssembloids to elucidate neuron-glia interactions DOI Creative Commons
Emmy Li,

Camila Benitez,

Steven Boggess

et al.

Neuron, Journal Year: 2025, Volume and Issue: 113(5), P. 701 - 718.e8

Published: Jan. 14, 2025

The complexity of the human brain makes it challenging to understand molecular mechanisms underlying function. Genome-wide association studies have uncovered variants associated with neurological phenotypes. Single-cell transcriptomics provided descriptions changes cells undergo during disease. However, these approaches do not establish mechanism. To facilitate scalable interrogation causal in cell types, we developed a 3D co-culture system induced pluripotent stem (iPSC)-derived neurons and glia, termed iAssembloids. Using iAssembloids, ask how glial neuronal interact control death survival. Our CRISPRi-based screens identified that GSK3β inhibits protective NRF2-mediated oxidative stress response elicited by high activity. We then investigate role APOE-ε4, risk variant for Alzheimer's disease, on find APOE-ε4-expressing astrocytes may promote hyperactivity as compared APOE-ε3-expressing astrocytes. This platform allows unbiased identification neuron-glia interactions.

Language: Английский

Citations

1
Synapse vulnerability and resilience underlying Alzheimer’s disease DOI Creative Commons
Raquel N. Taddei, Karen Duff

EBioMedicine, Journal Year: 2025, Volume and Issue: 112, P. 105557 - 105557

Published: Jan. 31, 2025

Synapse preservation is key for healthy cognitive ageing, and synapse loss represents a critical anatomical basis of dysfunction in Alzheimer's disease (AD), predicting dementia onset, severity, progression. viewed as primary pathologic event, preceding neuronal brain atrophy AD. Synapses may, therefore, represent one the earliest clinically most meaningful targets neuropathologic processes driving AD dementia. The highly selective particularly vulnerable synapses while leaving others, termed resilient, largely unaffected. Yet, anatomic molecular hallmarks resilient populations their association with changes (e.g. amyloid-β plaques tau tangles) memory remain poorly understood. Characterising selectively may be to understanding mechanisms versus enable development robust biomarkers disease-modifying therapies

Language: Английский

Citations

1
Astrocyte and oligodendrocyte pathology in Alzheimer's disease DOI Creative Commons

Rania Ziar,

Paul J. Tesar, Benjamin L.L. Clayton

et al.

Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown, P. e00540 - e00540

Published: Feb. 1, 2025

Astrocytes and oligodendrocytes, once considered passive support cells, are now recognized as active participants in the pathogenesis of Alzheimer's disease. Emerging evidence highlights critical role that these glial cells play pathological features Alzheimer's, including neuroinflammation, excitotoxicity, synaptic dysfunction, myelin degeneration, which contribute to neurodegeneration cognitive decline. Here, we review current understanding astrocyte oligodendrocyte pathology disease highlight research supports therapeutic potential modulating functions treat

Language: Английский

Citations

1
Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research DOI Creative Commons
Eun Sun Jung, Hayoung Choi, Inhee Mook‐Jung

et al.

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 27, 2025

Abstract Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play central role. These immune cells undergo reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, HIF-1α orchestrating these processes. Microglial metabolism adapts environmental stimuli, shifting oxidative phosphorylation glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts an energy sensor, coordinating lipid glucose metabolism. TREM2 APOE regulate microglial homeostasis, influencing Aβ clearance responses. LPL ABCA7, both associated AD risk, modulate processing cholesterol transport, linking neurodegeneration. PPARG further supports by regulating inflammatory Amino acid also contributes function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked pathology. Additionally, glucose-6-phosphate dehydrogenase regulates pentose phosphate maintaining redox balance activation. Dysregulated metabolism, influenced genetic variants APOE4, impair responses exacerbate progression. Recent findings highlight interplay regulators like REV-ERBα, which modulates inflammation, Syk, influences clearance. insights offer promising therapeutic targets, including strategies aimed at modulation, could restore function depending on stage. By integrating metabolic, immune, factors, this review underscores importance of immunometabolism AD. Targeting pathways provide novel for mitigating restoring function, ultimately paving way innovative treatments neurodegenerative diseases.

Language: Английский

Citations

1
The ROSMAP project: aging and neurodegenerative diseases through omic sciences DOI Creative Commons

Alejandra P. Pérez-González,

Aidee Lashmi García-Kroepfly,

Keila Adonai Pérez-Fuentes

et al.

Frontiers in Neuroinformatics, Journal Year: 2024, Volume and Issue: 18

Published: Sept. 16, 2024

The Religious Order Study and Memory Aging Project (ROSMAP) is an initiative that integrates two longitudinal cohort studies, which have been collecting clinicopathological molecular data since the early 1990s. This extensive dataset includes a wide array of omic data, revealing complex interactions between levels in neurodegenerative diseases (ND) aging. Neurodegenerative are frequently associated with morbidity cognitive decline older adults. Omics research, conjunction clinical variables, crucial for advancing our understanding diagnosis treatment diseases. summary reviews omics research—encompassing genomics, transcriptomics, proteomics, metabolomics, epigenomics, multiomics—conducted through ROSMAP study. It highlights significant advancements mechanisms underlying diseases, particular focus on Alzheimer's disease.

Language: Английский

Citations

5
Spatiotemporal Dysregulation of Neuron–Glia Related Genes and Pro-/Anti-Inflammatory miRNAs in the 5xFAD Mouse Model of Alzheimer’s Disease DOI Open Access
M. Di Ianni, Miriam Corraliza-Gómez, Tiago Costa-Coelho

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9475 - 9475

Published: Aug. 31, 2024

Alzheimer's disease (AD), the leading cause of dementia, is a multifactorial influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators gene expression play significant roles in AD onset progression. This exploratory study analyzed levels 28 genes 5 (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, miR-155-5p) related to pathology neuroimmune responses using RT-qPCR. Analyses were conducted prefrontal cortex (PFC) hippocampus (HPC)

Language: Английский

Citations

4
Cell–type specific profiling of human entorhinal cortex at the onset of Alzheimer's disease neuropathology DOI Creative Commons
Patricia Rodriguez‐Rodriguez, Wei Wang,

Christina Tsagkogianni

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Neurons located in layer II of the entorhinal cortex (ECII) are primary site pathological tau accumulation and neurodegeneration at preclinical stages Alzheimer's disease (AD). Exploring alterations that underlie early degeneration these cells is essential to develop therapies curb before symptom onset. Here we performed cell-type specific profiling human EC onset AD neuropathology. We identify an response amyloid pathology by microglia oligodendrocytes. Importantly, provide first insight into neuronal coincide with incipient pathology: signaling pathway for Reelin, recently shown be a major resilience gene dysregulated ECII neurons, while secreted synaptic organizer molecules NPTX2 CBLN4, emerging biomarkers, downregulated surrounding neurons. By uncovering complex multicellular landscape stages, this study paves way detailed characterization mechanisms governing NFT formation opens long-needed novel therapeutic avenues.

Language: Английский

Citations

0
LncRNA 3222401L13Rik Is Upregulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3 DOI Creative Commons
Sophie Schröder, M. Sadman Sakib, D. Krüger

et al.

Non-Coding RNA, Journal Year: 2025, Volume and Issue: 11(1), P. 2 - 2

Published: Jan. 9, 2025

Aging leads to cognitive decline and increased risk of neurodegenerative diseases. While molecular changes in central nervous system (CNS) cells contribute this decline, the mechanisms are not fully understood. Long non-coding RNAs (lncRNAs) key regulators cellular functions. Background/Objectives: The roles lncRNAs aging, especially glial cells, well characterized. Methods: We investigated lncRNA expression non-neuronal from aged mice identified 3222401L13Rik, a previously unstudied lncRNA, as upregulated astrocytes during aging. Results: Knockdown 3222401L13Rik primary revealed its critical role regulating genes for neuronal support synapse organization, function conserved human iPSC-derived astrocytes. A interacts with transcription factor Neuronal PAS Domain Protein 3 (Npas3), overexpression Npas3 rescues deficits lacking 3222401L13Rik. Conclusions: These data suggest that upregulation may help delay age-related decline.

Language: Английский

Citations

0