Alzheimer & Parkinson

Incentives modulate voluntary movement, yet the circuitry channeling these signals into motor output remains unclear. Classical models emphasize a closed-loop circuit (CLC) linking dorsal putamen (PUTd) with the motor cortex, but this pathway is anatomically segregated from affective processing regions. Anatomical and clinical evidence point to an alternative: an open-loop circuit (OLC) from ventral putamen (PUTv) that may route affective signals to the motor cortex. Here, we conducted two...

Ryanodine receptors (RYRs) are ER-resident Ca² ^(+) -release channels enriched in excitable cells, including neurons. RYR hyperactivity is implicated in early pathogenesis of disorders such as Alzheimer's disease (AD), which is associated with impaired autophagy. We recently uncovered a mechanism linking RYR activity to lysosome availability for autophagy. RYRs localize to ER - lysosome contact sites via direct binding to ATP6V0A1, a V-ATPase subunit that also suppresses RYR-mediated Ca² ^(+)...

Levodopa-induced dyskinesia (LID) is a debilitating complication of symptomatic therapy in Parkinson's disease. Although there is compelling evidence that striatal pathophysiology is a major driver of LID, the specific circuit mechanisms governing its expression remain obscure. To address this gap, molecular, cellular, and behavioral strategies were used to interrogate circuits in a mouse model of LID. These studies revealed that LID induction led to an upregulation of GluN2B-containing...

Microplastics (MPs), defined as plastic fragments less than 5 mm in diameter, are ubiquitous in the environment. As an emerging environmental pollutant, MPs can infiltrate the human body through multiple pathways, including inhalation, ingestion, dermal contact and bloodborne transmission.Correspondingly, MPs, which can penetrate the blood-brain barrier and enter the central nervous system (CNS), have been linked to the development of neurodegenerative diseases (NDs).In this review, we provide a...

Pathological accumulation of toxic SNCA species and loss of E3-ligase function of PRKN are two key features observed in Parkinson disease (PD). Here, we established the contribution of an E3-ligase-independent transcriptional function of PRKN in SNCA regulation. PRKN depletion decreased SNCA and GBA1 (glucosylceramidase beta 1) mRNA levels and reduced CMA-driven degradation of SNCA, thereby triggering the accumulation of its phosphorylated aggregation-prone toxic species. We established that...

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized future biomarker states remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike...

Dopaminergic neurons are fundamental in governing motivation, movement, and many aspects of cognition. The targeted modulation of dopaminergic signaling serves as a cornerstone in developing therapeutic interventions for conditions such as Parkinson's disease, schizophrenia, and addiction. Despite the pivotal role of dopaminergic neurons, the ultrastructure of dopaminergic synapses remains poorly understood. Here, we establish and utilize a cryo-correlative light and electron microscopy process...

Gut microbiota dysbiosis is a driving factor in Alzheimer's disease (AD), yet the mechanisms behind remain elusive. Emerging evidence highlights that outer membrane vesicles (OMVs) are critical mediators of microbiota-host communication. Here, we observed a reduction in a gut probiotic Escherichia coli Nissle 1917 (EcN)-like strain in AD patients, and its levels are positively associated with cognitive ability. The EcN OMVs containing outer membrane protein A (OmpA) translocate to the brain,...

Synaptic function and plasticity depend on the precise control of protein abundance and turnover, governed by the balance of synthesis and degradation. This review examines the regulatory mechanisms that maintain synaptic protein stability, focusing on the Ubiquitin-Proteasome System (UPS), autophagy-lysosomal pathways, and related proteolytic systems. We detail how key enzymes, including E3 ligases such as Nedd4-1, Mdm2, and Parkin, and deubiquitinating enzymes like USP46 and USP8, dynamically...

Traditional deep-brain stimulation via implanted electrodes can effectively treat neurological disorders, but surgical injury limits its clinical application. Here, we developed ultrasound-responsive piezoelectric nanoparticles for minimal-invasive and wireless neuromodulation. In the 6-OHDA-induced Parkinson's disease (PD) mouse model, these nanoparticles are injected into the subthalamic nucleus (STN) of the mouse brain. After ultrasound stimulation for several days, the motor behavior,...

Neurons and glia are distinct in their morphology, development and function, possessing unique transcriptomes and proteomes, but little is known about their metabolomes. The challenge of brain cell metabolic profiling is to obtain a large number of cells for reliable analysis. Here we purified microglia, astrocytes and neurons from mouse brains, identifying >70 metabolites through targeted metabolomics and 9,854 metabolite features via untargeted metabolomics. We systematically characterized...

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Alzheimer's disease (AD) is characterized by progressive cognitive decline, with synaptic dysfunction as the strongest correlate of clinical symptoms. The apolipoprotein E ε4 (ApoE4) allele is the most potent genetic risk factor for late-onset AD. Beyond its roles in amyloid-β aggregation and tau hyperphosphorylation, ApoE4 disrupts synaptic integrity by perturbing lipid metabolism, neuroimmune regulation, mitochondrial dynamics, and activity-dependent plasticity. These ApoE4-driven mechanisms...

Mitochondrial dysfunction is widely implicated in human disease, yet whether it plays a causal role and why effects are tissue-specific remain unclear. Here, we analyse over 15,000 RNA-sequencing datasets from 49 tissue types integrated with germline genetic data to investigate the impact of mitochondrial DNA (mtDNA) transcription on disease risk. We identify 25 nuclear genetic variants associated with mtDNA transcript abundance, revealing gene- and tissue-specific regulatory architectures. We...

Previous research on the genetic links between cognition and psychopathology has largely treated cognitive function as unitary, in part due to a lack of well-powered genome-wide association studies on specific cognitive domains, particularly crystallized knowledge (also known as crystallized intelligence). Here, we parse the genetics of cognitive test performance into components representing reaction time, fluid reasoning, and crystallized knowledge. This multivariate approach allows us to...

A blood biomarker reveals the mechanistic shift from amyloid to tau pathology.

With the aging of the global population, neurodegenerative diseases have become a major public health challenge. Currently, there are many limitations in the traditional treatment of neurodegenerative diseases, such as medicine, deep brain stimulation, transcranial magnetic stimulation, and transcranial direct current stimulation, including the inability to penetrate the blood-brain barrier (BBB) accurately and challenges in achieving precise and quantitative control during the treatment...

Monoclonal antibodies targeting amyloid-β, i.e., lecanemab and donanemab, have recently been approved for treating early Alzheimer's disease (AD). Though these antibodies are by many considered milestones in AD therapy, clinical approvals have been inconsistent due to ongoing debates over their clinical benefit and safety. The reported cognitive decline slowing is modest and often below the thresholds for clinically significant differences on outcome scales. Moreover, these therapies are linked...

Alzheimer's disease (AD) remains the most common neurodegenerative disorder. It is driven by complex molecular dysfunctions that includes amyloid aggregation, tau pathology, and neuroinflammation. It leads to cognitive deficits and memory loss in elderly people. Current treatments offer limited symptomatic relief. Hence, there is urgent need for innovative therapeutics and diagnostic approaches. Among emerging therapeutic targets, microRNAs (miRNAs) have pivotal role in regulating genes linked...

Plasma protein quantitative trait loci (pQTLs) have been integrated with genetic studies to prioritize proteins implicated in numerous human diseases. However, limited interaction between plasma and the central nervous system decreases the fluid's relevance for neurological disease. We compared the pQTL landscapes between plasma and cerebrospinal fluid (CSF), detecting widespread differences across fluids that translate to the identification and prioritization of proteins and pathways implicated...