Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology DOI Creative Commons
Matthew JM Rowan, Annie M Goettemoeller, Emmie Banks

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 6, 2023

Abstract Preventative treatment for Alzheimer’s Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in remain unknown. In human patients with Disease, one the earliest observed pathophysiological correlates to cognitive decline hyperexcitability1. mouse models, hyperexcitability has been shown entorhinal cortex, first cortical region impacted by Disease2-4. The origin early-stage disease why it preferentially emerges specific regions unclear. Using cortical-region cell-type- proteomics patch-clamp electrophysiology, we uncovered differential susceptibility human-specific amyloid precursor protein (hAPP) a model sporadic Alzheimer’s. Unexpectedly, our findings reveal that may result from intrinsic parvalbumin interneurons, rather than suspected layer II excitatory neurons. This PV interneurons hAPP, as could not be recapitulated increased murine APP expression. Furthermore, Somatosensory Cortex showed no such adult-onset hAPP expression, likely resulting PV-interneuron variability between two based on physiological proteomic evaluations. Interestingly, hAPP-induced was quelled co-expression Tau at expense pathological tau species. study suggests interventions targeting non-excitatory cell types protect symptoms downstream decline.

Language: Английский

Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease DOI Open Access
Beulah Leitch

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5549 - 5549

Published: May 19, 2024

Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role feedforward and feedback synaptic inhibition, preventing run away excitation neural networks. Hence, their dysfunction can lead hyperexcitability increased susceptibility seizures. PV+ also key players generating gamma oscillations, which synchronized oscillations associated with various cognitive functions. interneuron particularly vulnerable aging degeneration has been decline memory impairment dementia Alzheimer’s disease (AD). Overall, of disrupts normal excitatory/inhibitory balance within specific neurocircuits brain thus linked wide range neurodevelopmental neuropsychiatric disorders. This review focuses on dysfunctional inhibitory generation epileptic seizures potential as targets design future therapeutic strategies treat these Recent research using cutting-edge optogenetic chemogenetic technologies demonstrated they be selectively manipulated control restore activity brains animal models. suggests could important developing treatments for patients epilepsy comorbid disorders, such AD, where directly deficits.

Language: Английский

Citations

11
Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer’s disease DOI Creative Commons
Yona Levites, Eric B. Dammer,

Yong Ran

et al.

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(8), P. 101669 - 101669

Published: Aug. 1, 2024

Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare proteome network changes with the proteomes of amyloid β (Aβ)-depositing mice to identify conserved divergent networks identifying an Aβ responsome. Proteins most (M42) accumulate plaques, cerebrovascular (CAA), and/or dystrophic neuronal processes, overexpression two M42 proteins, midkine (Mdk) pleiotrophin (PTN), increases accumulation plaques CAA. proteins bind fibrils vitro, MDK PTN co-accumulate cardiac transthyretin amyloid. appear intimately linked deposition can regulate deposition, suggesting they are pathology modifiers thus putative therapeutic targets. We posit amyloid-scaffolded M42+ central mechanism mediating downstream pathophysiology AD.

Language: Английский

Citations

11
Proteomic Insight Into Alzheimer's Disease Pathogenesis Pathways DOI Creative Commons

Taekyung Ryu,

Kyungdo Kim, Nicholas Asiimwe

et al.

PROTEOMICS, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

ABSTRACT Alzheimer's disease (AD) is a leading cause of dementia, but the pathogenesis mechanism still elusive. Advances in proteomics have uncovered key molecular mechanisms underlying AD, revealing complex network dysregulated pathways, including amyloid metabolism, tau pathology, apolipoprotein E (APOE), protein degradation, neuroinflammation, RNA splicing, metabolic dysregulation, and cognitive resilience. This review examines recent proteomic findings from AD brain tissues biological fluids, highlighting potential biomarkers therapeutic targets. By examining landscape them, we aim to deepen our understanding support developing precision medicine strategies for more effective interventions.

Language: Английский

Citations

1
Aggregation-induced emission materials-based Electrochemiluminescence emitters for sensing applications: Progress, challenges and perspectives DOI
Xuan Wang,

Rongyan Wan,

Yan Tang

et al.

Coordination Chemistry Reviews, Journal Year: 2025, Volume and Issue: 531, P. 216520 - 216520

Published: Feb. 12, 2025

Language: Английский

Citations

1
Developing mRNA Nanomedicines with Advanced Targeting Functions DOI Creative Commons
Ji Wang, Lijun Cai, Ning Li

et al.

Nano-Micro Letters, Journal Year: 2025, Volume and Issue: 17(1)

Published: Feb. 21, 2025

The emerging messenger RNA (mRNA) nanomedicines have sprung up for disease treatment. Developing targeted mRNA has become a thrilling research hotspot in recent years, as they can be precisely delivered to specific organs or tissues enhance efficiency and avoid side effects. Herein, we give comprehensive review on the latest progress of with targeting functions. its carriers are first described detail. Then, mechanisms passive targeting, endogenous active outlined, focus various biological barriers that may encounter during vivo delivery. Next, emphasis is placed summarizing mRNA-based organ-targeting strategies. Lastly, advantages challenges clinical translation mentioned. This expected inspire researchers this field drive further development technology.

Language: Английский

Citations

1
Multifunctional spatial-potential resolved electrochemiluminescence biosensor for dual-channel simultaneous detection of hepatitis A virus and hepatitis C virus DNA DOI
Di Wu, Qianqian Cai, Jiajie Zhang

et al.

Sensors and Actuators B Chemical, Journal Year: 2024, Volume and Issue: 422, P. 136597 - 136597

Published: Sept. 10, 2024

Language: Английский

Citations

5
Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology DOI Creative Commons
Annie M Goettemoeller, Emmie Banks, Prateek Kumar

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 10, 2024

Language: Английский

Citations

5
Identification of ARHGEF11 (PDZ-RhoGEF) as an in vivo regulator of synapses and cognition DOI Creative Commons
Kathryn J. Bjornson, Bailey A. Kermath, Michael E. Cahill

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(4)

Published: Jan. 21, 2025

Given the influence of cognitive abilities on life outcomes, there is inherent value in identifying genes involved controlling learning and memory. Further, dysfunction a core feature many neuropsychiatric disorders. Here, we use combinatory silico approach to identify human gene targets that will have an especially high likelihood individually directly impacting cognition. This broad unbiased screen led specific identification ARHGEF11 , which encodes PDZ-RhoGEF. PDZ-RhoGEF largely RhoA-specific activator highly enriched dendritic spines, recent work identified hyperexpression prefrontal cortex bipolar disorder subjects, disease characterized by early emergence persistence scope dysfunction. characterize effects synaptic behavioral phenotypes, molecular biochemical mechanisms control PDZ-RhoGEF’s expression, spatial localization, enzymatic activity. Importantly, our direct regulators (miR-132 DISC1) themselves been repeatedly implicated phenotypes humans, including those caused several Taken together, findings indicate key convergence point among multiple cognition-relevant signaling cascades with potential translational significance.

Language: Английский

Citations

0
Simultaneous profiling of native-state proteomes and transcriptomes of neural cell types using proximity labeling DOI Creative Commons
Christina C. Ramelow, Eric B. Dammer,

Hailian Xiao

et al.

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

Published: Feb. 1, 2025

Abstract Deep molecular phenotyping of cells at transcriptomic and proteomic levels is an essential first step to understanding cellular contributions development, aging, injury, disease. Since proteome transcriptome level abundances only modestly correlate with each other, complementary profiling both needed. We report a novel method called simultaneous protein RNA –omics (SPARO) capture the cell type-specific simultaneously from in vitro vivo experimental model systems. This leverages ability biotin ligase, TurboID, biotinylate cytosolic proteins including ribosomal RNA-binding proteins, which allows enrichment biotinylated for proteomics as well protein-associated transcriptomics. validated this approach using well-controlled systems verify that proteomes transcriptomes obtained reflect ground truth, bulk transcriptomes. also show effect biological stimulus (e.g., neuroinflammatory activation by lipopolysaccharide) can be faithfully captured. applied obtain native-state two key neural types, astrocytes neurons, thereby validating application SPARO. Next, we used these data interrogate protein-mRNA concordance discordance across providing insights into groups processes exhibit uniform or patterns mRNA-protein discordance.

Language: Английский

Citations

0
Changes in the pH value of the human brain in Alzheimer’s disease pathology correlated with CD68-positive microglia: a community-based autopsy study in Beijing, China DOI Creative Commons
Xue Wang,

Xiangqi Shao,

Liang Yu

et al.

Molecular Brain, Journal Year: 2025, Volume and Issue: 18(1)

Published: Feb. 10, 2025

Abstract The microenvironment of the central nervous system is highly complex and plays a crucial role in maintaining function neurons, which influences Alzheimer’s disease (AD) progression. pH value brain critical aspect regulating various physiological processes. However, specific mechanisms this mechanism are not yet fully understood. To better understand relationship between AD, we analyzed frontal lobe AD pathology scores postmortem samples from 368 donors National Human Brain Bank for Development Function, 96 whom were diagnosed with pathology. Analysis revealed significant decrease patients, was strongly correlated β-amyloid plaques phosphorylated tau proteins. Here, elucidated differential protein expression level CD68-positive microglia control groups (t = 3.198, df 20, P 0.0045), its negatively (F 26.93, p 0.0006). Our findings that increased activation disrupted lysosomal homeostasis pathological tissue individuals may lead to pH.

Language: Английский

Citations

0