Alzheimer & Parkinson
Molecular pathways and diagnosis in spatially resolved Alzheimer's hippocampal atlas
We employed Stereo-seq combined with single-nucleus RNA sequencing (snRNA-seq) to investigate the gene expression and cell composition changes in human hippocampus with or without Alzheimer's disease (AD). The transcriptomic map, with single-cell precision, unveiled AD-associated alterations with spatial specificity, which include the following: (1) elevated synapse pruning gene expression in the fimbria of AD, with disrupted microglia-astrocyte communication likely leading to disorganized...
The absence of Pitx3 results in postnatal loss of dopamine neurons and is associated with an increase in the pro-apoptotic Bcl2 factor Noxa and cleaved caspase 3
Mesodiencephalic dopamine neurons (mdDA) of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) play critical roles in regulating movement and motivation. Pitx3 is an essential transcription factor required for proper embryonic development and terminal differentiation of mdDA neurons. Although Pitx3 is expressed in every mdDA neuron, its ablation results only in the absence of the SNc, not the VTA. The developmental stage at which the loss of SNc first becomes apparent, as...
Management of freezing of gait - mechanism-based practical recommendations
Freezing of gait (FOG) is a debilitating motor symptom that commonly occurs in Parkinson disease, atypical parkinsonism and other neurodegenerative conditions. Management of FOG is complex and requires a multifaceted approach that includes pharmacological, surgical and non-pharmacological interventions. In this Expert Recommendation, we provide state-of-the-art practical recommendations for the management of FOG, based on the latest insights into the pathophysiology of the condition. We propose...
Harnessing artificial intelligence to transform Alzheimer's disease research
No abstract
Efficacy and safety of passive immunotherapies targeting amyloid beta in Alzheimer's disease: A systematic review and meta-analysis
CONCLUSIONS: Anti-Aβ mAb therapy slows cognitive decline, but with small effect sizes, and raises potential concerns about ARIA and headaches.
A review: From old drugs to new solutions: The role of repositioning in alzheimer's disease treatment
Drug repositioning or drug reprofiling, involves identifying novel indications for approved and previously abandoned drugs in the treatment of other diseases. The traditional drug discovery process is tedious, time-consuming, risky, and challenging. Fortunately, the inception of the drug repositioning concept has expedited the process by using compounds with established safety profiles in humans, and thereby significantly reducing costs. Alzheimer's disease (AD) is a severe neurological disorder...
Modulation of CREB3L2-ATF4 heterodimerization via proteasome inhibition and HRI activation in Alzheimer's disease pathology
Alzheimer's disease (AD) pathology includes transcriptional changes in the neurons, which are in part caused by the heterodimerization of two stress response transcription factors, CREB3L2 and ATF4. We investigated the role of proteasome inhibition and the eIF2α-kinase HRI in the formation of CREB3L2-ATF4 in neurons exposed to soluble oligomeric Aβ(42). While HRI activation increased ATF4 expression, it decreased CREB3L2 and CREB3L2-ATF4 levels. Proteasome inhibition, induced by Aβ(42), leads to...
A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease
Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the...
Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer's disease
Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer's disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically...
Circular RNA aptamers targeting neuroinflammation ameliorate Alzheimer disease phenotypes in mouse models
Alzheimer disease (AD) therapy may benefit from optimized approaches to inhibit neuroinflammation. Small-molecule inhibitors of the proinflammatory molecule double-stranded RNA (dsRNA)-activated protein kinase R (PKR) have efficacy in AD models but their utility is compromised by adverse side effects. Here, we target PKR in two mouse models of AD using circular RNAs containing short double-stranded regions (ds-cRNAs), which are structurally similar to what we used previously to target PKR in...
Structural basis of oligomerization-modulated activation and autoinhibition of orphan receptor GPR3
G protein-coupled receptor 3 (GPR3) is a class A orphan receptor characterized by high constitutive activity in the G(s) signaling pathway. GPR3 has been implicated in Alzheimer's disease and the regulation of thermogenesis in human adipocytes, yet the molecular mechanisms underlying its self-activation and potential endogenous modulators remain unclear. In this study, we present cryo-electron microscopy (cryo-EM) structures of GPR3 in different oligomerization states, both in the absence and...
Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2
Targeting proteins to their final cellular destination requires transport mechanisms and nearly all lysosomal enzymes reach the lysosome via the mannose-6-phosphate receptor pathway. One of the few known exceptions is the enzyme β-glucocerebrosidase (GCase) that requires the lysosomal integral membrane protein type-2 (LIMP-2) as a proprietary lysosomal transporter. Genetic variations in the GCase encoding gene GBA1 cause Gaucher's disease (GD) and present the highest genetic risk factor to...
Neuroprotective mechanisms of exercise and the importance of fitness for healthy brain ageing
Ageing is a scientifically fascinating and complex biological occurrence characterised by morphological and functional changes due to accumulated molecular and cellular damage impairing tissue and organ function. Ageing is often accompanied by cognitive decline but is also the biggest known risk factor for Alzheimer's disease, the most common form of dementia. Emerging evidence suggests that sedentary and unhealthy lifestyles accelerate brain ageing, while regular physical activity, high...
Author Correction: Microglial mechanisms drive amyloid-beta clearance in immunized patients with Alzheimer's disease
No abstract
Denoising Search doubles the number of metabolite and exposome annotations in human plasma using an Orbitrap Astral mass spectrometer
Chemical exposures may affect human metabolism and contribute to the etiology of neurodegenerative disorders such as Alzheimer's disease. Identifying these small metabolites involves matching experimental spectra to reference spectra in databases. However, environmental chemicals or physiologically active metabolites are usually present at low concentrations in human specimens. The presence of noise ions can substantially degrade spectral quality, leading to false negatives and reduced...
Plasma p-tau217 and tau-PET predict future cognitive decline among cognitively unimpaired individuals: implications for clinical trials
Plasma p-tau217 and tau positron emission tomography (PET) are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In a head-to-head comparison study including nine cohorts and 1,474 individuals, we show that plasma p-tau217 and medial temporal lobe tau-PET signal display similar associations with cognitive decline on a global cognitive composite test (R²(PET) =...
Common and specific effects in brain oscillations and motor symptoms of tDCS and tACS in Parkinson's disease
Parkinson's disease (PD) leads to neurodegeneration and abnormal brain oscillations, causing motor dysfunction. Transcranial stimulation (transcranial direct current stimulation [tDCS]/transcranial alternating current stimulation [tACS]) may alleviate symptoms, but their oscillatory modulation mechanisms remain unclear. This randomized controlled trial (RCT) examines the effects of single-session tDCS/tACS on 60 PD patients, assigned to tDCS, tACS (20 Hz), or sham groups. Each receives 20-min...
Using Single-Cell RNA sequencing with Drosophila, Zebrafish, and mouse models for studying Alzheimer's and Parkinson's disease
Alzheimer's and Parkinson's disease are the most common neurodegenerative diseases, significantly affecting the elderly with no current cure available. With the rapidly aging global population, advancing research on these diseases becomes increasingly critical. Both disorders are often studied using model organisms, which enable researchers to investigate disease phenotypes and their underlying molecular mechanisms. In this review, we critically discuss the strengths and limitations of using...
IGF2-Reprogrammed Macrophages Ameliorate the Inflammatory Response and Protect Against the Neuroinflammatory Process in Parkinson's Disease Models
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra, leading to motor impairment. A hallmark of PD is the presence of misfolded α-synuclein (α-syn) proteins and their neurotoxic accumulations, contributing to neuronal loss. Additionally, the inflammatory response plays a critical role in modulating the neurodegeneration process in PD. Moreover, peripheral macrophages recognize α-syn, triggering chronic...
Presynaptic recycling pool density regulates spontaneous synaptic vesicle exocytosis rate and is upregulated in the presence of β-amyloid
Synapses represent a fundamental unit of information transfer during cognition via presynaptic vesicle exocytosis. It has been established that evoked release is probabilistic, but the mechanisms behind spontaneous release are less clear. Understanding spontaneous release is vital, as it plays a key role in maintaining synaptic connections. We propose a model framework for spontaneous release where the reserve pool geometrically constrains recycling pool vesicles, creating an entropic force that...
Alzheimer and Parkinson: Latest results from PubMed
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