Alzheimer & Parkinson

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...

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...

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...

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...

No abstract

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 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) =...

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...

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...

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...

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...

Finely tuned gamma (FTG) oscillations from the subthalamic nucleus (STN) and cortex in Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) are often associated with dyskinesia. Recently it was shown that DBS entrains gamma activity at 1:2 of the stimulation frequency; however, the functional role of this signal is not yet fully understood. We recorded local field potentials from the STN in 19 chronically implanted PD patients on dopaminergic medication during DBS, at rest,...

No abstract

Ageing is the most prominent risk factor for Alzheimer's disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in the brains of patients with AD remain elusive. Here we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains ageing hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-tau and...

No abstract

Evidence regarding the clinical validity of blood biomarkers of Alzheimer's disease (AD) in the general population is limited. We estimated the hazard and predictive performance of six AD blood biomarkers for incident all-cause and AD dementia-the ratio of amyloid-β 42 to amyloid-β 40 and levels of tau phosphorylated at T217 (p-tau217), tau phosphorylated at T181 (p-tau181), total tau, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)-in a cohort of 2,148 dementia-free...

The presence of neuronal Lewy bodies mainly composed of SNCA/α-synuclein aggregations is a pathological feature of Parkinson disease (PD), whereas reducing SNCA protein levels may slow the progression of this disease. We hypothesized that compounds enhancing SNCA's interaction with MAP1LC3/LC3 May increase its macroautophagic/autophagic degradation. Here, we conducted small molecule microarray (SMM)-based screening to identify such compounds and revealed that the compound R406 could decrease...

Synaptic Rho guanosine triphosphatase (GTPase) guanine nucleotide exchange factors (RhoGEFs) play vital roles in regulating the activity-dependent neuronal plasticity that is critical for learning. Ephexin5, a RhoGEF implicated in the etiology of Alzheimer's disease and Angelman syndrome, was originally reported in neurons as a RhoA-specific GEF that negatively regulates spine synapse density. Here, we show that Ephexin5 activates both RhoA and Cdc42 in the brain. Furthermore, using live imaging...

Despite remarkable progress in the biomarker field in recent years, local validation of plasma biomarkers of Alzheimer's disease (AD) and dementia is still lacking in Latin America. In this longitudinal cohort study of 145 elderly Brazilians, we assess the diagnostic performance of plasma biomarkers, based on clinical diagnosis and CSF biomarker positivity. Follow-up data of up to 4.7 years were used to determine performance in predicting diagnostic conversions. Participants were clinically...

The amyloid hypothesis has been a leading narrative concerning the pathophysiological foundation of Alzheimer's and Parkinson's disease. At the two ends of the hypothesis lie the functional protein monomers and the pathology-defining amyloid fibrils, while the early stages of protein aggregation are populated by polymorphic, transient and neurotoxic oligomers. As the structure and activity of oligomers are intertwined, here we show oligomers arising from liquid-liquid phase separation and...