GLP-1 receptor signaling restores aquaporin 4 subcellular polarization in reactive astrocytes and promotes amyloid β clearance in a mouse model of Alzheimer's disease.

The physiological actions of a gut hormone, glucagon-like peptide-1 (GLP-1), in Alzheimer's disease (AD) brain remain poorly understood, although GLP-1 receptor (GLP-1R) expression in this organ has been shown in several experimental studies. Therefore, we explored whether the GLP-1R signaling promotes the clearance of amyloid β (Aβ) (1-42) which is a core pathological hallmark of AD, focusing on the water channel protein aquaporin 4 (AQP4) localized to astrocyte endfeet perivascular membranes in intact brain. First, we confirmed that Glp1r mRNA is predominantly expressed at perivascular site of astrocytes in normal mouse cerebral cortex through in situ hybridization analysis.

Age- and amyloid-β-dependent initiation of neurofibrillary tau tangles: an improved mouse model of Alzheimer's disease without mutations in .

Introducing heterozygous humanized tau to App knock-in mice results in the first mouse model of Alzheimer's disease in which age and amyloid-β pathology interact to initiate neurofibrillary tau tangle pathology, not dependent on mutations in MAPT. Gradual progression from amyloid-β to tau pathology in NLFTau mice opens possibilities for understanding processes precipitating clinical stages of Alzheimer's disease and development of translatable therapies to prevent the onset of tau pathology.

Future projections for mammalian whole-brain simulations based on technological trends in related fields.

Large-scale brain simulation allows us to understand the interaction of vast numbers of neurons having nonlinear dynamics to help understand the information processing mechanisms in the brain. The scale of brain simulations continues to rise as computer performance improves exponentially. However, a simulation of the human whole brain has not yet been achieved as of 2024 due to insufficient computational performance and brain measurement data.

Sparse Bayesian correntropy learning for robust muscle activity reconstruction from noisy brain recordings.

Sparse Bayesian learning has promoted many effective frameworks of brain activity decoding for the brain-computer interface, including the direct reconstruction of muscle activity using brain recordings. However, existing sparse Bayesian learning algorithms mainly use Gaussian distribution as error assumption in the reconstruction task, which is not necessarily the truth in the real-world application. On the other hand, brain recording is known to be highly noisy and contains many non-Gaussian noises, which could lead to large performance degradation for sparse Bayesian learning algorithms.

Quantitative analysis and machine learning-based interpretation of EEG signals in coma and brain-death diagnosis.

Electroencephalography (EEG) reflects brain activity and is crucial for diagnosing states such as coma and brain-death. However, the clinical interpretation of EEG signals faces challenges due to the patients' faint brain activity and the complexities of the intensive care unit environment, further compounded by the absence of quantified standards for signal analysis. This study developed an improved denoise method tailored to the characteristics of Coma/Brain-Death EEG signals.

Functionally overlapping intra- and extralysosomal pathways promote bis(monoacylglycero)phosphate synthesis in mammalian cells.

Bis(monoacylglycero)phosphate (BMP) is a major phospholipid constituent of intralumenal membranes in late endosomes/lysosomes, where it regulates the degradation and sorting of lipid cargo. Recent observations suggest that the Batten disease-associated protein CLN5 functions as lysosomal BMP synthase. Here, we show that transacylation reactions catalyzed by cytosolic and secreted enzymes enhance BMP synthesis independently of CLN5.

Stimuli-responsive self-regulating assembly of chiral colloids for robust size and shape control.

Most synthetic self-assemblies grow indefinitely into size-unlimited structures, whereas some biological self-assemblies autonomously regulate their size and shape. One mechanism of such self-regulation arises from the chirality of building blocks, inducing their mutual twisting that is incompatible with their long-range ordered packing and thus halts the assembly's growth at a certain stage. This self-regulation occurs robustly in thermodynamic equilibrium rather than kinetic trapping, and therefore is attractive yet elusive.

Common protein-altering variant in GFAP is associated with white matter lesions in the older Japanese population.

The genetic architecture of white matter lesions (WMLs) in Asian populations has not been well-characterized. Here, we performed a genome-wide association study (GWAS) to identify loci associated with the WML volume. Brain MRI and DNA samples were collected from 9479 participants in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD).

Why nature evolved GPI-anchored proteins: unique structure characteristics enable versatile cell surface functions.

It remains a mystery why nature evolved the unique structural characteristics of GPI-anchored proteins (GPI-APs) and continues to sustain the complex, energy-intensive process of synthesizing these proteins. GPI-APs, despite their small size, rely on the coordinated activity of nearly 30 genes for their synthesis and remodeling, raising important evolutionary questions. The biological advantages of GPI-APs lie in their ability to rapidly redistribute across the cell membrane, localize within lipid rafts, utilize unique intracellular trafficking pathways, and function as both membrane-bound and soluble proteins.

Widespread 3'UTR capped RNAs derive from G-rich regions in proximity to AGO2 binding sites.

The 3' untranslated region (3'UTR) plays a crucial role in determining mRNA stability, localisation, translation and degradation. Cap analysis of gene expression (CAGE), a method for the detection of capped 5' ends of mRNAs, additionally reveals a large number of apparently 5' capped RNAs derived from locations within the body of the transcript, including 3'UTRs. Here, we provide direct evidence that these 3'UTR-derived RNAs are indeed capped and widespread in mammalian cells.

Relationship between regional volume changes and water diffusion in fixed marmoset brains: an in vivo and ex vivo comparison.

Ex vivo studies of the brain are often employed as experimental systems in neuroscience. In general, brains for ex vivo MRI studies are usually fixed with paraformaldehyde to preserve molecular structure and prevent tissue destruction during long-term storage. As a result, fixing brain tissue causes microstructural changes and a decrease in brain volume.

Novel pharmacologic inhibition of lysine-specific demethylase 1 as a potential therapeutic for glioblastoma.

Lysine-specific demethylase 1 (LSD1/KDM1A) is a pivotal epigenetic enzyme that contributes to several malignancies including malignant glioma. LSD1 is a flavin adenine dinucleotide dependent histone demethylase that specifically targets histone H3 lysine (K) 4 mono- (me1) and di-methylation (me2) and H3K9me1/2 for demethylation. Herein we report the development of an LSD inhibitor, S2172, which efficiently penetrates the blood-brain barrier.

The fly brain lands in Tokyo: A report on the 3rd Asia Pacific Drosophila Neurobiology Conference.

The third Asia Pacific Drosophila Neurobiology Conference (APDNC3) was held in the Wako Campus of RIKEN in Tokyo, Japan, from February 27th to March 1st, 2024. While APDNC2 was held in Taiwan in 2019, the global coronavirus pandemic enforced a long hiatus. Hence, APDNC3 was a much-anticipated meeting that attracted ~218 scientists from 18 different countries and regions, 154 from outside Japan.

The Icelandic Mutation (APP-A673T) Is Protective against Amyloid Pathology In Vivo.

A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene () can protect against Alzheimer's disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation.

Generation of human induced pluripotent stem cell lines derived from two glucose transporter 1 deficiency syndrome patients.

Glucose transporter 1 deficiency syndrome (GLUT1DS), caused by impaired glucose transport at the blood-brain barriers, leads to various central nervous system dysfunctions. A comprehensive understanding of the underlying disease pathogenesis is still lacking. In this study, we have generated GLUT1DS-specific human induced pluripotent stem cells (hiPSCs) derived from two patients.

Progressive Amyloid-β Accumulation in the Brain leads to Altered Protein Expressions in the Liver and Kidneys of APP knock-in Mice.

Impaired hepatic and renal function influence Alzheimer's disease (AD) progression; however, whether AD progression affects these important organ functions remains unclear. Here, we investigated the impact of AD progression, characterized by brain amyloid-beta (Aβ) accumulation, on liver and kidney function of App (APP-KI) mice using quantitative proteomics. SWATH-based quantitative proteomics revealed changes in mitochondrial, drug metabolism, and pharmacokinetic-related proteins in mouse liver and kidneys during the early (2-month-old) and intermediate (5-month-old) stages of Aβ accumulation.

Digital detection of Alzheimer's disease using smiles and conversations with a chatbot.

In super-aged societies, dementia has become a critical issue, underscoring the urgent need for tools to assess cognitive status effectively in various sectors, including financial and business settings. Facial and speech features have been tried as cost-effective biomarkers of dementia including Alzheimer's disease (AD). We aimed to establish an easy, automatic, and extensive screening tool for AD using a chatbot and artificial intelligence.

A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development.

Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11B, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11b mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46 cells in the thymus and reduction in TBR1 neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b.

EVA1-Antibody Drug Conjugate is a new therapeutic strategy for eliminating glioblastoma-initiating cells.

Background: The discovery of glioblastoma (GBM)-initiating cells (GICs) has impacted GBM research. These cells are not only tumorigenic, but also exhibit resistance to radiotherapy and chemotherapy. Therefore, it is crucial to characterize GICs thoroughly and identify new therapeutic targets.

Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors.

The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution has woven the LC into wide-ranging neural circuits that influence functions as broad as autonomic systems, the stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility that LC activity is inherently similar across species, and furthermore that age, sex, and brain state influence LC activity similarly across species.

Prescription trends in Japanese advanced Parkinson's disease patients with non-motor symptoms: J-FIRST.

Background: Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice.

Methods: We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS.