Alzheimer & Parkinson

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,...

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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...

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here we identify PSMF1 as a gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal...

Disruptions in the glymphatic system and its downstream meningeal lymphatic drainage pathway, crucial for brain waste clearance, are linked to the pathogenesis of Alzheimer's disease (AD), yet the underlying mechanisms remain unclear. Abnormal calcium dynamics in astrocytes represents an early event in the mouse models of AD. Here we show functional association between amyloid-β-induced elevation of Ca^(2+) dynamics in medial prefrontal cortex astrocytes and glymphatic dysfunction in cognitively...

Biomarkers to determine underlying frontotemporal lobar degeneration (FTLD) tau or TAR DNA-binding protein (TDP) pathology during life are needed to advance clinical trials targeting specific FTD pathologies. For this purpose, we developed a new ultrasensitive immunoassay to quantify acetylated tau at lysine 174 (AcTau174) in cerebrospinal fluid (CSF). In a sporadic cohort (n = 513), AcTau174 concentrations were higher in all dementia groups (FTLD-TDP, FTLD-Tau, Alzheimer's disease (AD), mild...

Plasma phosphorylated tau 217 (pTau217) is an excellent biomarker of Alzheimer's disease (AD) pathology, but it remains uncertain whether pTau217 can predict amyloid-β (Aβ) and tau accumulation prior to Aβ positron emission tomography (PET) positivity. Here, we leverage data from a well-characterized prospective cohort of cognitively unimpaired older adults to examine mass spectrometry-based plasma %pTau217 (pTau217/non-phosphorylated-Tau217×100) relative to changes in Aβ/tau PET and cognition....

Astrocytes are key partners for neurons and can impact diseases such as Alzheimer's disease (AD), as they exhibit multiple reactive changes. Recent single cell/nucleus genomics analyses evidence astrocyte subpopulations coexisting in normal and AD brains. However, the signaling cascades controlling them, their functional characteristics and roles in AD are still unknown. Here, thanks to astrocyte-specific reporters for STAT3 and NF-kB signaling pathways, two regulators of astrocyte reactivity,...

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