Alzheimer & Parkinson

Complement component 1q (C1q), the initiator of the classical complement cascade, mediates synaptic elimination in development and disease, yet the triggers for its deposition on synapses remain unclear. Using in vivo chemogenetics, we demonstrate that neuronal hyperactivity induces region-specific, C1q-dependent synapse loss in the adult hippocampus. Suppressing perforant pathway hyperactivity in a mouse model of Alzheimer's disease reduced local amyloid-β amounts and C1q deposition and...

Repressor Element 1-Silencing Transcription factor (REST) emerges as a metabolism-sensitive transcriptional hub that supports basal mitophagy, mitochondrial quality, and synaptic function in neurons. In Alzheimer's disease, REST becomes mislocalized and functionally impaired, coinciding with early defects in mitochondrial quality control. Activation of the NAD^(+) -SIRT1 axis enhances REST nuclear activity, restores its mitochondrial and neuroprotective gene programs, and attenuates pathological...

Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease...

CONCLUSION: Disrupted brain RAS homeostasis induces pro-inflammatory microglial remodeling and worsens PD neurodegeneration. This study reveals novel pathogenic mechanisms and identifies promising therapeutic targets for PD treatment.

Amyloid-β (Aβ) fibrils primarily composed of Aβ(1-40) and Aβ(1-42) form the core of senile plaques in Alzheimer's disease. Aβ(1-40) fibrils may exhibit significant polymorphism influenced by sample preparation conditions, complicating atomic resolution structural characterization. To establish a reliable structural baseline, we developed a protocol for expressing and purifying recombinant Aβ(1-40) that forms monomorphic fibrils under physiological conditions (pH 7.4). We present a...

Sleep deprivation (SD), together with inevitable stress inherent to conventional SD protocols, can induce oxidative stress and inflammation, thereby increasing the risk of premature death. However, the source and signaling pathways underlying reactive oxygen species (ROS) generation remain unclear. Here, we demonstrate that both mechanical and thermogenetic SD, along with possible stress induced by both protocols, lead to initial ROS accumulation in Drosophila gut subregions, including the...

Insufficient understanding of α-synuclein turnover mechanisms has impeded successful clinical translation for Parkinson's disease (PD). Here, we pinpointed cholesterol 25-hydroxylase (CH25H) as a pivotal regulator of α-synuclein degradation. Through bulk RNA sequencing of substantia nigra tissue from the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, along with reanalysis of published datasets from induced pluripotent stem cell-derived astrocytes of patients with PD, we...

Autosomal monoallelic gene expression and asynchronous replication between alleles are established features of imprinted genes and genes regulated by allelic exclusion. Inactivation/Stability Centers (I/SCs) are recently described autosomal loci that exhibit epigenetic regulation of allelic expression and replication timing, with differences that can be comparable to those observed between the active and inactive X chromosomes . Here, we characterize >100 autosomal loci with allele-specific...

Alzheimer's disease (AD) remains a progressive neurodegenerative disorder without effective disease-modifying therapies. Epidemiological evidence indicates that regular resistance exercise substantially reduces AD risk, an effect potentially mediated by insulin-like growth factor-1 (IGF-1). However, the complete mechanistic pathway from exercise-induced peripheral IGF-1 synthesis to its central neuroprotective actions has not been systematically integrated. This review provides a comprehensive...

Bridge-like lipid transfer proteins (BLTPs) play fundamental roles in cellular lipid redistribution between organellar membranes. They comprise bridge domains spanning organelles at contact sites that allow lipids to transit through the cytosol between adjacent membranes. The assembly of BLTPs into complexes with adaptor proteins enables lipid transfer. To address the mechanisms underlying the assembly and regulation of BLTP complexes, we used cryo-EM to resolve the structure of one such BLTP,...

There is growing evidence that long-acting mimetics of the gut-derived incretin hormones GLP-1 and GIP act as disease-modifying therapies for Alzheimer's disease (AD). Here, we temporally characterize the efficacy of the approved incretin receptor agonists semaglutide, a GLP-1R agonist, and tirzepatide, a GLP-1R/GIPR co-agonist, in preventing AD progression. In 5xFAD mice treated for 2 or 4 months, both incretin therapies lower body weight and improve glucose tolerance, yet neither compound...

CONCLUSIONS: Conclusions are limited by substantial heterogeneity in the assessment of frailty, sarcopenia, AD biomarkers, and a lack of longitudinal data. Future studies are needed that include longitudinal analyses, consensus in AD biomarker, frailty and sarcopenia assessments, and incorporation of novel AD biomarkers, in particular tau and neuroinflammation, to help clarify these relationships.

Clinical trial design (CTD) is a time-consuming process that requires substantial domain expertise. Large-scale real-world data (RWD), such as electronic health records (EHR), encodes practice-based evidence that is of tremendous value to CTD. In recent years, many machine learning methods have been developed to extract such real-world evidence (RWE) from the RWD to inform CTD, but they still need to be communicated with the domain experts extensively in an iterative manner to be further refined...

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The renin-angiotensin system (RAS), classically known for its role in cardiovascular and fluid homeostasis, also regulates neuronal homeostasis in the central nervous system (CNS), where its dysregulation contributes to PD pathogenesis. The emerging evidence links excessive activation of the brain RAS in PD, where sustained activation of the angiotensin II (Ang II)/angiotensin type-1 receptor (AT1R) axis promotes oxidative stress, neuroinflammation, mitochondrial dysfunction, and blood-brain...

Alzheimer's disease (AD) currently lacks effective curative treatments. Icariin (ICA), a flavonoid from Epimedium, has been widely investigated in AD animal models with emerging neuroprotective potential. However, the methodological quality, reporting rigor, and translational reliability of this preclinical evidence have not yet been systematically evaluated. Studies investigating ICA in AD were retrieved from eight databases up to May 12, 2026. The reporting quality, risk of bias, and study...

White matter (WM) abnormalities have emerged as a critical element in Alzheimer's disease (AD) pathogenesis, shifting from their former status as a passive consequence to an active contributor to disease progression. Notably, microstructural WM alterations, detectable early via advanced neuroimaging techniques such as diffusion tensor imaging, frequently precede overt gray matter atrophy and cognitive decline, highlighting their potential as early contributors to AD pathogenesis. The origins of...

Flexible pressure sensors are key components of Internet of Things systems for monitoring environmental and physiological signals, yet simultaneously achieving a high sensitivity, a fast response time, and a high mechanical durability remains challenging owing to the lack of sophisticated structural designs that balance sensing performance and robustness. Here, we demonstrate a multiscale artificial spider web (MASW) fabricated via copper-mesh-assisted electrospinning of biodegradable polylactic...

Brain maintenance - the preservation of brain structure or function relevant to cognitive performance - remains challenging to quantify. Here, we propose a domain-general brain maintenance index derived by jointly modelling the longitudinal co-evolution of ageing-related atrophy (via medial temporal lobe to ventricle ratio, MTLV-ratio), white matter hyperintensities (WMH), and global cognition assessed by the preclinical Alzheimer's cognitive composite (PACC5) using latent growth curve...