Alzheimer & Parkinson

Alzheimer's disease (AD) is the most common neurodegenerative disease with unclear regulatory mechanisms at the cell-type level. A multi-omics model called single nucleotide polymorphisms (SNPs)-transcriptomic-single-nucleus ribonucleic acid sequencing (snRNA-seq) integration (STSNI) is proposed to identify SNPs-related biomarkers and regulatory mechanisms in AD. Differential expression analysis identified differentially expressed genes (DEGs) between AD patients and healthy controls (HCs) in...

Parkinson's disease (PD), characterized by α-synuclein (α-syn) pathology, affects millions of people worldwide. While current treatments mainly symptomatically address the motor aspects of PD, they lack efficacy in delaying or halting the degenerative process. Ferroptosis, a type of programmed cell death characterized by iron-dependent lipid peroxidation, has been previously linked to PD. Advancing the development of neuroprotective treatments hinges on comprehending the interplay between PD's...

As aging is the primary risk factor for many chronic diseases, geroscience aims to target aging to delay age-related decline. Here, we identify Cyrene (dihydrolevoglucosenone), a sustainable, biocompatible solvent, as a novel geroprotective compound. Cyrene extends lifespan and healthspan in C. elegans, improving locomotor function and resistance to oxidative, thermal, osmotic, genotoxic, and proteotoxic stress. It also confers protection in neurodegenerative models of Alzheimer's, Parkinson's,...

Alzheimer's disease (AD), first identified by Dr. Alois Alzheimer in 1906, has evolved from a rare presenile dementia to a global health crisis affecting over 58 million people as of 2020, with projections reaching 152 million by 2050. Manuscript offers a comprehensive overview of AD, tracing its historical origins, epidemiological trends, pathophysiological mechanisms, diagnostic advancements, and therapeutic strategies. The pathogenesis of AD is multifactorial, involving amyloid-β plaque...

White matter hyperintensities (WMH) are a magnetic resonance imaging (MRI) sign associated with cognitive complaints in the Alzheimer's Disease (AD) continuum, including the pre-dementia steps. Cardiovascular and neurodegenerative pathophysiology have been postulated as relevant factors in the origin of WMH in AD. However, this evidence comes mainly from northern global populations, where the epidemiological profile differs from other geographical regions. This study explores the relationship...

Parkinson's disease (PD) is a neurodegenerative disease that manifests motor and non-motor symptoms due to the progressive loss of dopaminergic neurons in the substantia nigra. While its pathogenesis is multifactorial, with genetic as well as environmental components, more and more evidence suggests that nutrition and diet play an important role in regulating both the development and progression of the disease through crosstalk with genetics, a term known as nutrigenomics. This review discusses...

Cellular senescence contributes to age-related neurodegeneration, yet its manifestation varies across brain cell types and senescence-inducing stressors. Here, we investigated senescence hallmarks in five human brain cell lines - astrocytes, endothelial cells, microglia, oligodendrocytes, and dopaminergic-like neurons - using chronic 5-Bromodeoxyuridine treatment and validated our findings in primary cells and alternative toxin-induced models. Principal component analysis and transcriptional...

Transcriptome- and proteome-wide association studies (TWAS/PWAS) have proven successful in prioritizing genes and proteins whose genetically regulated expression modulates disease risk, but they ignore potential co-expression and interaction effects. To address this limitation, we introduce the co-expression-wide association study (COWAS) method, which can identify pairs of genes or proteins whose genetically regulated co-expression is associated with complex traits. COWAS first trains models to...

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Alzheimer's disease (AD) is one of the brain's neurodegenerative diseases. It is distinguished by a progressive mental, social, and behavioral deterioration. It affects the person's capacity, thinking, attention, reasoning, social behavior and functionality to achieve independence. The classical diagnosis process of AD consists of variety of neuroimaging scan approaches such as computerized tomography, magnetic resonance imaging and positron emission tomography. Classical cerebrospinal fluid...

Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and aggregation of alpha-synuclein (αSyn). Compelling evidence showed that αSyn aggregates exist as distinct conformational strains in different synucleinopathies. Recently, we reported that the αSyn Seed Amplification Assay (αSyn-SAA) can amplify and distinguish αSyn strains from PD and MSA. In this study, we investigate whether MSA-seeded, SAA-amplified αSyn fibrils...

While the clinical utility of conventional antibody therapies is undeniable, their therapeutic potential is often constrained high antigen loads and the recycling of antibody-antigen complexes via neonatal Fc receptor (FcRn). Here, we present a platform, based on a design similar to bispecific antibodies, FcγRIIb-Targeting Chimeras (FcRTAC). These constructs recognise antigens with one arm and bind FcγRIIb with the other arm to harness the unique endocytic properties of FcγRIIb to direct the...

The progressive accumulation of amyloid beta (Aβ) plaques is a hallmark of Alzheimer's disease (AD). However, the biochemical mechanisms of their formation and the consequences associated with plaque formation remain elusive. In female 5xFAD and APP^(NL-G-F) mice, we map region-specific, plaque-associated lipids with large molecular coverage including isomers. We describe a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization...

Prime editing offers versatile genome modifications with therapeutic potential; yet its use to modulate neural circuitry remains underexplored. Here, we used adeno-associated viral vectors to deliver prime editors into the mouse brain and introduced the naturally occurring Adrb1^(A187V) variant of the β1-adrenergic receptor, linked to short sleep in humans and mice. Editing reached up to 28.1% in the cortex six months after intracerebroventricular injection and increased excitability of...

UBB^(+1), a ubiquitin variant protein resulting from a frameshift in the ubiquitin-B gene, is a pathological hallmark of Alzheimer disease (AD). At the cellular level, UBB^(+1) disrupts the ubiquitin-proteasome system while inducing autophagy. Notably, UBB^(+1) itself is secreted via autophagosome-like vesicles. Here, we demonstrate that UBB^(+1) can be removed from the cell by degradative and secretory autophagy. Sequestosome 1 (SQSTM1)/p62 functions as a pivotal ubiquitin receptor for...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal cell death, brain atrophy, and cognitive decline. Aggregation of Tau protein in neurons is a critical factor in the pathogenesis of AD. Tau aggregates increase as the disease progresses and contribute to neuronal cell death. This study investigated the role of ubiquitin-specific protease 10 (USP10) in Tau pathology and neuronal viability in AD. We found that the expression of USP10 was reduced in the...

The glymphatic system was initially considered as a perivascular channel, responsible for the clearance of substances within the brain. With the deepening comprehension of the functions of the extracellular space (ECS) and the discovery of meningeal lymphatic vessels and subarachnoid lymphatic-like membrane, it is proposed that the glymphatic system should be a complex system encompassing the perivascular space, ECS, and lymphatic-like structures, and it plays crucial roles in the delivery of...

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is marked by dopaminergic neuron loss and α-synuclein aggregation. Although Braak staging based on Lewy body pathology stratifies disease progression, clinical variability persists. Identifying stage-specific molecular signatures is essential for developing effective progressive biomarkers. Here, we integrated midbrain transcriptomic data from microarray, bulk RNA-seq, and snRNA-seq platforms. Subsequently, to...

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Chaperone-mediated autophagy (CMA), once considered a secondary or auxiliary degradation pathway, is now recognized as a central regulator of synaptic proteostasis. A recent study by Khawaja et al. (2025) in Nature Cell Biology provides compelling evidence that CMA actively remodels the synaptic proteome in a sex-specific manner. Using a conditional knockout strategy based on Lamp2a-floxed mice crossed with a Camk2a-Cre driver line to achieve excitatory neuron-specific deletion of Lamp2a in...