Alzheimer & Parkinson

Thermogenic proteins are down-regulated under thermal stress, including PGC1α· However, the molecular mechanisms are not fully understood. Here, we addressed that chaperone-mediated autophagy could regulate the stability of PGC1α under thermal stress. In mice, knockdown of Lamp2a, one of the two components of CMA, in BAT showed increased PGC1α protein and improved metabolic phenotypes. Combining the proteomics of brown adipose tissue (BAT), structure prediction, co-immunoprecipitation- mass...

Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapy development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated...

The dynamic behaviour of amyloid-β (Aβ) plaques in Alzheimer's disease remains poorly understood, and accumulation and distribution of Aβ plaques must be inferred from in vitro pathological changes in brain tissue. In situ detection of Aβ plaques in live imaging is challenging because of the lack of adequate probes. Here we report the design of unimolecular quinoline-malononitrile-based Aβ probes, termed QMFluor integrative framework, that binds in vivo to Aβ plaques, making them detectable via...

CONCLUSION: TLN is safe and well-tolerated in general. This prospective phase I trial revealed non-allergic habituating acute infusion reactions at the second, third, or fourth treatment that can be prevented by a slower rate of infusion. Importantly, the exploratory results suggest a consistent improvement of signs and symptoms of PD.

The research focused on exploring the differences and relationships between gut microbiota and metabolites at various stages of Alzheimer's disease (AD), specifically using APP/PS1 mice at the ages of 6 months and 10 months. To assess metabolites in serum and cortex, and to evaluate gut microbiota profiles in cecal content, UPLC-MS/MS and 16S rRNA sequencing techniques were utilized, respectively. Findings indicated that, in comparison to younger mice, serum concentrations of L-Leucine, thymine,...

Metabolites, lipids, and glycans are fundamental but interconnected classes of biomolecules that form the basis of the metabolic network. These molecules are dynamically channeled through multiple pathways that govern cellular physiology and pathology. Here, we present a framework for the simultaneous spatial analysis of the metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. This workflow integrates a computational platform, the Spatial Augmented...

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Biological definitions of neurological diseases are now becoming a reality, although still in the research phase. This development will recategorize neurological diseases, providing objective diagnostics and the promise of therapeutics that target biological mechanisms - similar to the strategy that has proven successful in tumours and other conditions. In this Perspective article, we discuss this development for dementias with dominant Lewy pathology, as the availability of biological assays...

Sex differences in Parkinson's disease (PD) offer insights into mechanisms of dopaminergic cell resilience. Female dopamine (DA) neurons are more resilient via mechanisms that remain unclear. Here, we discovered key sex and regional differences in mitochondrial generation of cytotoxic reactive oxygen species (ROS) and their implications for DA neuron resilience using the Drosophila model. While aging raised mitochondrial ROS in DA neurons of both sexes, we observed a sexually dimorphic response...

Substance use disorders disrupt the dopaminergic system of the human brain, which plays a central role in movement and reward processing, altering perception, and cognition. The pleasurable urge to move to music, known as groove, relies on dopamine for reward, anticipation, beat perception, and motor system activity. Using a well-established paradigm, which shows an inverted-U relationship between groove and musical complexity, we investigated how dopamine downregulation from long-term cocaine...

Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, studies using singlecell profiling techniques have begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown that molecularly defined DA subtypes within the substantia nigra (SNc) display distinctive anatomic and functional properties, and differential vulnerability in Parkinson's disease (PD)....

Alzheimer's disease (AD) is the most common neurodegenerative pathology in older persons. The accumulation of amyloid β (Aβ) plaques is a major contributor to AD development. The RNA-binding protein HuD/ELAVL4 has been implicated in the formation of Aβ plaques, but its role in AD is unclear. Here, we report that ablation of HuD from CAMK2A^(+) neurons (HuDcKO) in the 5xFAD mouse model of AD results in a significant reduction of Aβ plaques and the alleviation of some AD-associated behaviors....

Leucine, a branched-chain amino acid (BCAA), exhibits paradoxical effects in Alzheimer's disease (AD), demonstrating both neuroprotective and neurotoxic roles. While prior studies have investigated leucine's systemic and metabolic impacts, its influence on brain structure remains unexplored. This study aimed to fill this critical gap by examining the relationship between serum leucine levels, brain volume metrics, and cognitive performance in individuals across the AD continuum. Serum leucine...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Metabolic dysfunctions, particularly type 2 diabetes mellitus (T2DM), have been implicated in AD pathogenesis, highlighting the potential for novel therapeutic approaches targeting shared underlying mechanisms. Here, we investigate sodium-glucose cotransporter 2 (SGLT2) inhibition as a therapeutic strategy for AD using Enavogliflozin, a potent SGLT2 inhibitor, in the 5XFAD mouse model....

Alzheimer's disease (AD) is initiated by amyloid-beta (Aβ) accumulation in the neocortex; however, the cortical layers and neuronal cell types first susceptible to Aβ remain unknown. Using in vivo two-photon Ca^(2+) imaging in the visual cortex of AD mouse models, we found that cortical layer 5 neurons displayed abnormally prolonged Ca^(2+) transients before substantial plaque formation. Neuropixels recordings revealed that these abnormal transients were associated with reduced spiking and...

The onset of Alzheimer's Disease and Frontotemporal Dementia is closely associated with the aggregation of tau, a multifunctional protein essential for neuronal stability and function. Given the role of tau aggregation in neurodegeneration, understanding the mechanisms behind its fibril formation is crucial for developing therapeutic interventions to halt or reverse disease progression. However, the structural complexity and diverse aggregation pathways of tau present significant challenges,...

Computational research tools have reached a level of maturity that enables efficient simulation of neural activity across diverse scales. Concurrently, experimental neuroscience is experiencing an unprecedented scale of data generation. Despite these advancements, our understanding of the precise mechanistic relationship between neural recordings and key aspects of neural activity remains insufficient, including which specific features of electrophysiological population dynamics (i.e., putative...

The recent emergence of wearable devices will enable large scale remote brain monitoring. This study investigated whether multimodal wearable sleep recordings could help screening for Alzheimer's disease (AD). Measurements were acquired simultaneously from polysomnography and a wearable device, measuring electroencephalography (EEG) and accelerometry (ACM) in 67 elderly without cognitive symptoms and 35 AD patients. Sleep staging was performed using an AI model (SeqSleepNet), followed by feature...

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