Alzheimer & Parkinson

Alzheimer's disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, especially in genes associated with clonal hematopoiesis (CH). These sSNVs were associated with clonal expansion and carried by both microglia-like brain macrophages (MLBMs) in multiple brain regions as well as paired blood,...

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic and inflammatory mechanisms, potentially mediated by the gut microbiota, yet the neurobiological impact of comorbid AD+T2DM microbiota from elderly donors remains unexplored. Fecal microbiota from healthy, AD, T2DM, and AD+T2DM postmenopausal female donors (aged 56-89 years) was transplanted into antibiotic-treated male mice. Behavioral testing, blood profiling, hippocampal neurotrophic gene expression, and 16S rRNA...

We propose a computational framework for spatial niche analysis (SpaNiche) in spatial transcriptomics data to uncover colocalization patterns and infer potential ligand-receptor interactions. SpaNiche leverages graph-regularized joint non-negative matrix factorization to integrate information from cell abundance and ligand-receptor expression, identifying spatial colocalization patterns among cell types while providing insights into associated ligand-receptor interactions. Besides, SpaNiche...

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and...

Neuroinflammation plays a key role in Alzheimer's disease (AD) and many other neurodegenerative disorders. Chronic activation of astrocytes and microglia fuels neuronal damage via cytokine secretion, oxidative stress, and proteolysis, yet glial inflammatory regulation remains poorly understood. Using chemoproteomics, we identified CK2, particularly the brain-enriched catalytic subunit CK2α2, as a key driver of astrocytic inflammation. CK2 enhances NF-κB activity by phosphorylating NF-κB S529 and...

Diagnostic models using primary care routine clinical variables have been limited in their ability to identify Alzheimer's disease (AD) patients. In this study, we sought to better understand the effect of mild cognitive impairment (MCI) on the predictive performance of AD diagnostic models. We sourced data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. CatBoost was used to assess the utility of routine clinical variables that are accessible to primary care physicians, such...

The subthalamic nucleus (STN) is a critical hub for inhibitory control, implicated in decision making under conflict and impulsivity. Delta frequency oscillations have also been associated with inhibitory control processes, yet the relationship between human STN neuronal activity and local delta frequencies during response inhibition remains unresolved. Here we recorded STN neurons and local field potentials in patients with Parkinson's disease performing a stop-signal reaction time task during...

The aggregation of amyloid proteins into fibrillar and oligomeric aggregates is linked to a number of neurodegenerative diseases. While the disease onset remains elusive in many cases, an understanding of the driving forces for the aggregation may help finding possible causes. While effects on amyloid formation kinetics are more commonly studied, gaining insights into these driving forces require a thermodynamic approach with equilibrium measurements. Here we investigate the temperature...

Embodied accounts of morality propose that corporeal self-awareness helps restrain immoral actions. The Sense of Agency (SoA)-the feeling of controlling one's actions and their consequences-drops when individuals harm others. However, whether modulating SoA shifts moral behavior remains unclear. Parkinson's Disease (PD) offers a unique model to address this question, because dopaminergic dysfunction affects both SoA and moral decision-making. We tested 23 individuals with PD in ON and OFF...

The Davos Alzheimer's Collaborative (DAC) Egypt Cohort (DAC-Egypt) is a newly established longitudinal study of cognitive aging in a community-based convenience sample of older Egyptian adults. The cohort's purpose is to characterize trajectories of cognitive decline and dementia risk factors in an understudied population, filling a critical gap in aging research in the Middle East. Participants (n = 1,530) aged 55 and above were recruited via regionally diverse convenience sampling, with...

Parkinson's disease (PD) is a major cause of disability. GBA1 variants are the most common genetic risk factor for PD and increase the risk up to 30-fold. Why only approximately 20% of GBA1 variant carriers develop PD remains unknown. Here, by combining clinical and fecal metagenomics data from 271 patients with PD, from 43 carriers of GBA1 variants not manifesting PD symptoms (GBA-NMC) and from 150 healthy controls, and using an innovative microbiome analysis, combining differential abundance...

Double-stranded nucleic acids can undergo transitions from canonical B/A-forms to alternate left-handed Z-DNA/Z-RNA (Z-NAs). Z-NAs are implicated in processes such as neuroinflammation in Alzheimer's disease, Lupus Erythematosus, microbial biofilms, and type I interferon-mediated human pathologies. Since endogenous Z-NA sensors like the Zα domain can induce B-to-Z transitions, monoclonal antibodies (mAbs) Z-D11 and Z22 have been regarded as conformation-specific tools to confirm Z-NA in situ,...

No abstract

Parkinson's disease (PD) is characterised by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Lewy bodies- the defining neuropathological hallmark of PD-are chiefly composed of aggregated forms of α-synuclein (α-syn). Despite the widespread presence of α-syn pathology, neurodegeneration is often selective, and the mechanisms underlying the vulnerability of specific neuronal populations in PD remain poorly understood. This review critically...

Ferroptosis promotes the progression of Parkinson's disease (PD) through its unique regulatory pathways. Biochanin A (Bioch A) has long attracted the attention of researchers due to its neuroprotective effects. However, whether Bioch A can treat PD by inhibiting ferroptosis and the underlying mechanism remain unclear. This study aimed to investigate whether Bioch A exerts a neuroprotective effect on PD by activating the Sirt1/Nrf2/GPX4 signaling pathway to inhibit ferroptosis. Behavior was...

The nicotinamide adenine dinucleotide (NAD^(+)) hydrolase sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is the central executioner of pathological axon degeneration and is allosterically activated by an increased nicotinamide mononucleotide (NMN)/NAD^(+) ratio. DNA damage induces NAD^(+) loss and an increased NMN/NAD^(+) ratio by hyperactivating poly(ADP-ribose) polymerase 1 (PARP1), which triggers the parthanatos cell death pathway. Multiple mechanistically distinct...

PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration...

Alzheimer's disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores...

Gaining precise control of gene expression is crucial in biomedical applications. However, spatiotemporal precision remains challenging. Here, we present a remotely controlled in vivo gene switch responsive to electromagnetic fields (EMFs) that enables precise spatiotemporal activation of target genes. We uncovered the EMF-inducible gene switch activation mechanism via a CRISPR-Cas9 screen, identifying cytochrome b5 type B (Cyb5b) as an essential mediator likely acting as an EMF sensor. The...

Multiple system atrophy (MSA) is a rare, age-related neurodegenerative disease that shares clinical and pathological features with Parkinson's disease (PD) but presents a more devastating disease course. To elucidate the distinct cellular pathophysiology, we performed single-nucleus RNA sequencing on postmortem striatal brain tissue from 7 MSA and 12 PD patients, and 10 non-neurological cases. Here, we show significant compositional differences in astroglia and microglia subtypes, while...