Journal of Neurochemistry最新文献

BACE1 is an indispensable enzyme for the production of β-amyloid peptides by initiating the cleavage of amyloid precursor protein at the β-secretase site. Targeting BACE1 inhibition is therefore a therapeutic strategy for treating patients with Alzheimer's disease. However, several clinical trials using brain-penetrable BACE1 inhibitors have failed due to a lack of efficacy. Previous studies, including our own, have shown that both global and neuron-specific BACE1 inhibition in mice leads to impairments in synaptic strength and spine density. In this study, we investigate the effects of BACE1 inhibition on activity-dependent synaptic vesicle exocytosis and endocytosis using a synapto-pHluorin mouse model. Our results demonstrate impaired synaptic release in BACE1-deficient mice. Furthermore, transcriptomic analysis reveals a significant downregulation of genes related to synapse structure and function. Pathway analysis suggests that BACE1 deficiency significantly downregulates neurexin-neuroligin pathway, which can modulate docking and release of synaptic vesicles at the presynaptic compartment. Our findings suggest that BACE1 inhibition may lead to deficits in synaptic vesicle exocytosis due to the downregulation of key synaptic proteins.

Psychiatric disorders affect millions of people worldwide. Despite widespread use of conventional treatments targeting monoaminergic systems, remission rates remain low, and many individuals experience treatment resistance or relapse. Consequently, there has been growing interest in the involvement of other systems, with exacerbated immune responses and barrier alterations reported in clinical settings and preclinical models. Indeed, emerging evidence supports disruption of the blood–brain barrier (BBB) and intestinal barrier in the etiology and progression of psychiatric conditions, notably major depression, bipolar disorder, and generalized anxiety. The BBB is a highly selective structure whose integrity is maintained by endothelial cells, astrocytes, pericytes, and cellular adhesion molecules. Loss of BBB integrity has been increasingly recognized not only as a marker of psychiatric disorders but also as a contributing factor in their development. The BBB and intestinal barrier share anatomical features and functions, especially with the gut–vascular barrier, which remains understudied. Intestinal barrier dysfunction is a hallmark of inflammatory bowel disease (IBD), a condition with a high rate of comorbidity with psychiatric disorders. Both barriers are characterized by similar cellular components and signaling pathways regulating permeability. Psychological stress, a major risk factor for psychiatric conditions and IBD, renders the BBB and intestinal barrier hyperpermeable, feeding a vicious cycle of exacerbated inflammation and ultimately, mood changes as discussed here. We highlight key signaling pathways linked to barrier development and function, including Wnt/β-catenin, VEGF, and FGF-2, and argue that they may contribute to the pathophysiology of mental disorders and IBD, and could be targeted to develop innovative diagnostic tools and treatments. Key limitations and knowledge gaps are reviewed. To sum up, barrier-related alterations have long been reported in clinical studies in psychiatry and are now receiving increasing attention at the mechanistic level, as they may be relevant to uncovering new therapeutic targets beyond traditional monoamine-focused treatments.

Loss of function in oligodendroglial cells is a pathological hallmark of demyelinating and neurodegenerative diseases. A significant pool of oligodendrocyte precursor cells is maintained in the adult brain following developmental myelination. This population of cells provides plasticity to the myelin network that is crucial for healthy brain function and facilitates myelin repair following demyelination. G protein-coupled receptors (GPCRs) represent a major target class in the druggable genome and are widely expressed in oligodendroglia. Targeting GPCRs involved in remyelination presents a tractable approach for the development of disease-modifying medicines. Despite this, the functional outcomes of GPCR modulation in oligodendroglia remain to be deeply explored, which has hindered the development of remyelinating therapies.

This review highlights signaling modalities at the blood–brain and blood–cerebrospinal fluid barriers, with reference to the cell types and pathways recruited under steady state conditions and in obesity. We summarize areas of consensus and unresolved questions surrounding the temporal progression of neuroinflammation and the propagation of neuroimmune responses between different cell types and circuits. While data on the reversibility of these changes is scarce, we review the available data on reinstatement of neuroimmune homeostasis following physiological and pharmacological interventions. Published data from preclinical models aligns with evidence implicating middle age as a critical period for the impact of obesity on brain function in humans. Elucidating the metabolic and immune signatures associated with neurological dysfunction could identify novel biomarkers and inform the development of targeted strategies to improve healthspan in obese individuals.

Preclinical studies suggest that taurine may exert neuroprotective effects. However, its relevance to dementia risk in human populations remains unclear. We investigated the associations between mid-life dietary taurine intake, circulating taurine concentrations, and the risk of late-life all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in a large prospective cohort. This study utilized data from 27 786 participants of the Malmö Diet and Cancer Study with baseline examination from 1991 to 1996. Dietary taurine intake was estimated from a detailed diet history and adjusted for energy intake. Plasma taurine concentration was measured in a subset of 3693 individuals. Dementia diagnoses were ascertained through the Swedish National Patient Register and validated by memory clinic physicians. Cox proportional hazards models assessed associations with dementia risk, adjusting for potential confounders including APOE ε4 status, lifestyle factors, and comorbidities. Over a median 25-year follow-up, 3224 participants developed dementia. No significant associations were found between dietary taurine intake or plasma taurine concentrations and the risk of all-cause dementia, AD, or VaD. Circulating taurine concentrations were only weakly correlated with dietary intake, suggesting a predominant role of endogenous taurine synthesis and metabolism. Our findings fail to support a protective role for taurine intake against dementia in humans. Further studies are warranted to examine potential effects under specific pathological conditions or with high-dose supplementation.

The implementation of touchscreen platforms in co-clinical trials for rodents (i.e., mice and rats) and humans to assess cognitive functions presents an opportunity to overcome barriers present in conventional clinical trials. To better visualize the progress made in this area, this review proposes a systematic synthesis of the comparability of touchscreen cognitive assessment studies applied to both humans and rodents in a co-clinical framework. To accomplish this objective the Ovid, PubMed, Scopus and ScienceDirect databases were searched, in English, and without publication date limit and registered on the International Prospective Register of Systematic Review (PROSPERO) under the number CRD420250650537. The screening resulted in 5 cross-sectional studies and 1 randomized controlled trial (RCT) included, which were assessed for methodological quality and risk of bias using the Joanna Briggs Institute (JBI) critical appraisal tools. The data acquired in this review reinforce the potential of touchscreen platforms for cognitive assessment across human and rodent models. Behavioral flexibility and visuospatial cognition excelled in terms of comparability. The scarcity of studies and methodological diversity represent significant gaps in the field. Regardless, the available data highlight important opportunities for advancing translational research in cognition with a co-clinical approach.

Synaptic plasticity and memory formation require de novo protein synthesis. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) promotes mRNA translation initiation in the central nervous system. Recent research has uncovered that excitatory neurons, inhibitory neurons, and glia play distinct roles in modulating synaptic strength and encoding long-term memory via mTORC1 signaling. In this review, we discuss the mechanisms by which mTORC1 regulates translation initiation in the brain and its cell type-specific roles in shaping distinct forms of synaptic plasticity and memory. We also consider how dysregulated translational control contributes to neurological disorders and explore emerging technologies for therapeutic modulation of the mTORC1 pathway.

Alzheimer's disease (AD) is more than just amyloid and tau. While often described as a disease of metabolic dysfunction, AD can more accurately be described as a disorder of metabolic inflexibility that leads to bioenergetic failure. In the healthy brain, neurons, glia, and vascular cells dynamically share and switch between different fuel sources (e.g., glucose, lactate, ketones, and fatty acids) to match functional demand. In AD, this adaptability is progressively lost because cellular metabolism is actively reprogrammed to support neuroinflammatory and disease-associated processes at the cost of neuronal function. Microglia, in particular, upregulate glycolytic metabolism, alter lipid handling, and prioritize immune functions, which actively depletes the brain's energy supply. These adaptations are initially compensatory but ultimately trap the brain in a rigid metabolic program that deprioritizes neuronal support. This metabolic shift unfolds along a biphasic trajectory: early, glia-driven hypermetabolism aligned with inflammation, followed by late-stage brain hypometabolism and energy collapse that leads to neuronal dysfunction. System-level consequences include altered excitability, decreased network connectivity, sleep disruption, and cognitive decline. Critically, these changes feed forward to accelerate AD pathogenesis: glycolytically biased microglia and stressed neurons promote amyloid-β production, tau release, and protein aggregation, adding to metabolic rigidity. Evidence from human neuroimaging studies, brain/cerebral spinal fluid (CSF) multi-omic studies, and preclinical studies demonstrate that shifts in glycolytic flux, tricarboxylic acid cycle (TCA) intermediates, and lipid metabolism parallel amyloid and tau pathology and cognition decline. We hypothesize that these metabolic programs, while initially protective, are chronically maladaptive yet reversible. We propose that restoring metabolic flexibility can mitigate amyloid and tau pathology, neuronal loss, and functional decline. Ongoing preclinical studies and clinical trials are actively exploring metabolism as a therapeutic target in AD. Collectively, these findings define AD as a disorder of metabolic inflexibility, where adaptive shifts in cellular metabolism become pathologically rigid and drive disease progression, while offering a promising target for therapeutic intervention in AD.