Alzheimer & Parkinson

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by progressive memory loss and cognitive decline. With the global population ageing, the prevalence of AD continues to rise, posing a significant public health challenge. Historically, AD research has centred on two hallmark pathological features: β-amyloid (Aβ) deposition and tau protein hyperphosphorylation. However, repeated failures of therapeutic strategies targeting these pathways in clinical trials have prompted a...

A 'gut-brain axis' is an intricate bidirectional connection between the gut and the central nervous system, serving as a key pathway for signal exchange. However, current in vitro models do not fully capture these dynamic interactions, limiting mechanistic insight and therapeutic testing. Here, we show a 3D human gut-brain-vascular microphysiological platform that integrates lumenized villus-like intestinal barrier, blood vascular-astrocyte interactions, and brain tissue to model...

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In recent years, the immune metabolism of central nervous system cells has gained increasing attention from researchers. Microglia (MG) are innate immune cells of the central nervous system. They can metabolize a wide range of energy substrates. The pathways and products generated through these processes play a critical role in the onset and progression of Alzheimer's disease (AD). This paper provides a comprehensive review of metabolic reprogramming in MG during AD. It focuses on the three...

Brainstem white matter (WM) bundles are essential conduits for neural signals that modulate homeostasis and consciousness. Their architecture forms the anatomic basis for brainstem connectomics, subcortical circuit models, and deep brain navigation tools. However, their small size and complex morphology, compared to cerebral WM, makes mapping and segmentation challenging in neuroimaging. As a result, fundamental questions about brainstem modulation of human homeostasis and consciousness remain...

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Cerebral amyloid angiopathy (CAA) is a neurodegenerative condition characterized by amyloid-β (Aβ) deposition in small vessel walls, often coexisting with Alzheimer's disease due to impaired Aβ clearance. However, the spatial distribution of Aβ within the human brain remains unclear as the vascular network's complexity and scale hinder visualization by conventional thin-slice analysis. To address this, we performed three-dimensional (3D) volumetric imaging of the cerebrovascular network and Aβ...

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PINK1-dependent activation of PRKN/parkin on depolarized mitochondria causes mitophagy. The deficiency of NME3, a nucleoside diphosphate kinase/NDPK on the outer mitochondria membrane (OMM), is associated with a fatal neurodegenerative disorder. Here, we report that NME3 deficiency impairs p-S65-ubiquitin (Ub)-dependent PRKN binding on depolarized mitochondria without involving the loss of Ub phosphorylation by PINK1. Our mechanistic investigation revealed that NME3 interacts with PLD6/MitoPLD...

How the memory engram is organized at the cell-assembly level to support not only encoding of learned information but also memory flexibility remains elusive. Here, we propose a novel engram model encoded by two orthogonal learning-recruited neuronal ensembles in the mouse dentate gyrus. Reactivation of the Fos-tagged ensemble promotes memory retrieval, whereas reactivation of the Npas4-dependent ensemble drives forgetting, with manipulation of the forgetting ensemble inversely shifting memory...

The native microbiome influences numerous host processes, including neurological function. However, its impacts on diverse brain cell types remain poorly understood. Here, we performed single-nucleus RNA sequencing on the hippocampus of wild-type, germ-free mice, revealing the microbiome-dependent transcriptional landscape across all major neural cell types. We found conserved impacts on key adaptive immune and neurodegenerative transcriptional pathways. Mono-colonization with select indigenous...

Recent advances in high-throughput technologies have led to an increased generation of biological data across genomics, transcriptomics, proteomics, epigenomics, and metabolomics. However, a major challenge remains: effectively integrating these multi-omics datasets to allow a more holistic understanding of the complex, interconnected mechanisms underlying human diseases. Neurodevelopmental, neurodegenerative, and psychiatric disorders are particularly multifactorial and heterogeneous, making...

Deep brain stimulation (DBS) is effective for treating neurological and psychiatric disorders. However, its tethered configuration, invasiveness, and limited tissue compatibility motivate wireless, minimally invasive alternatives. Here, we develop an in situ-gelled injectable conductive hydrogel (ICH), enabling wireless neuromodulation via electric-field localization under volume conduction. The ICH forms in vivo through bio-catalyzed polymerization and electrostatic self-assembly, yielding a...

Parkinson's disease (PD) is an incurable neurological disorder that often begins insidiously with sleep disturbances and somatic symptoms, progressing to whole-body motor and cognitive symptoms^(1-5). Dysfunction of the somato-cognitive action network (SCAN)-which is thought to control action execution^(6,7) by coordinating arousal, organ physiology and whole-body motor plans with behavioural motivation-is a potential contributor to the diverse clinical manifestations of PD. To investigate the...

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Biofluid-based biomarkers have transformed neurodegenerative disease research and care, providing insights into the molecular underpinnings of Alzheimer's disease (AD) and other neurodegenerative dementias. This Review provides an update on recent developments in biofluid-based biomarkers for amyloid-β (Aβ) pathology, tau pathology, neurodegeneration, glial reactivity, α-synuclein pathology, TAR DNA-binding protein 43 (TDP-43) pathology, synaptic pathophysiology and cerebrovascular...

Genome-wide association studies strongly implicate neuroinflammation in late-onset Alzheimer's disease (LOAD). Genetic risk loci for LOAD are enriched for genes expressed in microglia, but the relationship among microglial LOAD risk genes has been unclear. We found that the N-terminal SH2 domain of INPP5D, an important LOAD risk gene, directly interacted with the cell death regulator RIPK1 at p-Y383 to suppress RIPK1 kinase activation. Microglial INPP5D deficiency cell-autonomously promoted...

Dietary capsaicin intake appears to affect the pathogenesis of Alzheimer's disease (AD), while the underlying mechanisms remain unclear. Here, we found in human cohorts that moderate-to-high level of dietary capsaicin intake was associated with improved cognitive performance. Similarly, long-term oral capsaicin administration in male 5×FAD mice ameliorated AD-like pathologies and reshaped gut microbial composition. Gut microbiota transfer from capsaicin-treated mice produced similar effects of...

Microglial phagocytosis exerts essential roles in neurodegeneration, but how phagocytic processes may reciprocally regulate microglia remains incompletely understood. Here, we report that microglial response in the mouse model of pathological axonal degeneration depends on the phagocytic receptor MerTK. The MerTK-triggered downstream phospholipase C signal is sufficient to induce the up-regulation of PU.1 and IRF8, the two central transcription factors governing microglial functions. Chromatin...

Tyrosine nitration alters the structure, function, and cellular localization of proteins and is implicated in the pathology of multiple diseases [G. Ferrer-Sueta et al., Chem. Rev. 118, 1338-1408 (2018), H. Ischiropoulos, Arch. Biochem. Biophys. 356, 1-11 (1998), I. Griswold-Prenner et al., J. Biol. Chem. 299, 105038-10554 (2023)]. Although protein nitration is assumed to proceed via nonspecific chemical mechanisms, it is highly selective, suggesting the possibility of enzymatic catalysis. Here,...