Alzheimer & Parkinson

Transcranial ultrasound stimulation (TUS) is an emerging method for non-invasive neuromodulation of deep brain structures. However, to date, there is no evidence that TUS can directly modulate disease-related pathological oscillations in the same direction as known therapies. Inspired by clinical deep brain stimulation, in this randomised controlled cross-over study we probed the effects of pallidal TUS pulsed at 130 Hz on subthalamic beta-band activity, a biomarker in Parkinson's Disease (PD)...

In early drug discovery, in vitro screening is frequently used, but selected candidates often fail in vivo. Induced pluripotent stem cell (iPSC)-based disease models offer improved physiological relevance; however, the high costs of media and differentiation procedures limit large-scale testing. Here, we develop a high-throughput conditioned-media-based screening system-the High-throughput screening technology for Aggregation Inhibitors of Diseased cell-derived Aggregative Proteins (HaiDap)...

LRRK2 (encoding leucine-rich repeat kinase 2) variants are the most common genetic cause of Parkinson's disease (PD). Lowering LRRK2 levels and/or inhibiting LRRK2 activity may modify PD-associated neuropathology. BIIB094 (ION859), an antisense oligonucleotide, targets LRRK2 mRNA for degradation. REASON was a first-in-human randomized phase 1 study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal BIIB094 in patients with PD. In part A, 40 participants...

Alzheimer's disease (AD) is a highly prevalent progressive neurodegenerative disorder with unclear etiology, complex symptoms, and limited treatment options. Early pathological processes in AD emerge long before the onset of overt cognitive and motor symptoms and involve the accumulation of amyloid-β oligomers and neurofibrillary tangles, accompanied by neuroinflammation and neuronal loss. Importantly, the brain reward system comprises cortical and subcortical structures that share neurochemical...

Neurodegenerative diseases (NDs) pose clinical challenges due to their complexity and molecular heterogeneity. Here, we present a pan-neurodegeneration atlas (PanNDA) from multilayer, deep proteomic analysis of 2,279 human brain samples spanning 6 major NDs: Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal lobar degeneration with TDP-43 pathology, progressive supranuclear palsy with tau pathology, vascular dementia, and Parkinson's disease. PanNDA integrates data from whole...

Alterations to the protein and microRNA cargo of extracellular vesicles (EVs) occur in Alzheimer's disease (AD) and may contribute to disease progression. We previously showed that ingestion of amyloid-beta (Aβ) by both murine and human astrocytes leads to alterations to the protein cargo of EVs that induce significant neuronal impairment and apoptosis. Here, we hypothesised that pathological changes to the microRNA cargo of astrocyte-derived EVs (ADEVs) would also occur following exposure of...

β-Amyloid (Aβ) and tau pathologies are hallmark lesions of Alzheimer's disease (AD) and they develop in human brain following differential spatiotemporal trajectories. Accordingly, young/adult-onset tau-independent β-amyloidosis is rare. We encountered four such cases among 397 banked brains, with the donors died of hematological malignances (blood cancers) or cardiovascular diseases. To explore the pathological implication, we examined 17 brains (10-87 year-old, y) from blood cancer patients...

Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors,...

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BACKGROUND: Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease.

Engineered exosomes are modified extracellular vesicles designed to enhance targeting and cargo delivery, and they have been proposed as a therapeutic strategy for Alzheimer's disease. We systematically reviewed preclinical animal studies evaluating engineered exosomes, synthesized evidence from comparisons with disease models and with natural exosomes, and reported the study in accordance with the PRISMA 2020 checklist. Outcomes included spatial learning and memory assessed by the Morris water...

Parkinson's disease (PD) is a progressive, multisystem neurodegenerative disorder characterized not only by motor impairments but also by a broad spectrum of debilitating non-motor symptoms, including cognitive decline. The cognitive function depends on neuronal plasticity, which is tightly regulated by multiple signaling systems, among which the endocannabinoid system (ECS) plays a significant role. Over the past three decades, substantial evidence has accumulated regarding how endogenous...

The neurotrophin receptor p75 (p75NTR) plays dual, context-dependent roles in the nervous system that are regulated by ligand binding, co-receptor interactions, and microenvironmental cues. During neurodevelopment, synaptic plasticity, and in neurodegenerative disorders, p75NTR orchestrates opposing cellular responses: it can support neuronal homeostasis through pro-survival pathways, while also initiating apoptotic and inflammatory cascades that exacerbate disease progression. In Alzheimer's...

Organic anion-transporting polypeptide transporters (SLCO/OATPs) function as cellular gatekeepers, regulating intestinal absorption, hepatic and renal clearance, and the tissue distribution of drugs and metabolites in the human body. However, the mechanisms underlying substrate selection within the SLCO superfamily remain unclear, hampering efforts to rationalize the interaction of drugs and metabolites with these transporters. SLCO2A1 (also known as OATP2A1) is responsible for the distribution...

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder and the leading cause of dementia, strongly associated with amyloid β-peptide (Aβ) accumulation in the cerebrum. In most cases, this aggregation is primarily due to inefficiencies in the degradation and clearance of Aβ, notably its transport across the blood-brain barrier (BBB) into the bloodstream. This study investigates the role of P-glycoprotein (P-gp), a key transporter in transporting Aβ across endothelial-cell monolayers,...

TDP-43 pathology defines limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and frequently co-occurs with Alzheimer's disease neuropathologic change (ADNC), yet the molecular consequences of overlapping pathology remain unclear. We performed biochemical and proteomic analyses of postmortem hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups. Cryptic exon (CE) inclusion was quantified across eight TDP-43-regulated transcripts and related to...

Mutations in the phospholipase A2 group VI (PLA2G6) gene have been linked to autosomal recessive Parkinson's disease (PD), yet the molecular mechanisms remain poorly understood. This study provides the in vitro and in vivo evidence, specifically in dopaminergic neurons derived from patients with PD, that PLA2G6 loss-of-function disrupts the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), a critical regulator of Ca^(2+) transfer and energy homeostasis. This study demonstrates...

Biomolecular condensates formed via liquid-liquid phase separation (LLPS) are essential for cellular organization. α-Synuclein, an amyloidogenic protein linked to Parkinson's Disease (PD), undergoes phase separation at high concentrations, but the influence of lipid membranes on this process remains unclear. Here, combining in vitro reconstitution, cell biology, and simulations, we show that membranous interfaces promote α-Synuclein condensation at physiologically relevant sub-critical...

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Transglutaminase 2 (TG2) is implicated in synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies, as it promotes α-Synuclein (α-Syn) aggregation in vitro, and evidence for its activity is detected in Lewy bodies in human postmortem brains. Additionally, TG2 overexpression exacerbates α-Syn toxicity in double transgenic mice, while TG2 deletion mitigates the phenotype of α-Syn transgenic mice. Considering that TG2 is a multidomain and multifunctional protein, the...