Alzheimer & Parkinson

CONCLUSIONS: We provide our systematic testing framework as an open-source, publicly available tool that can be utilised to offer novel insights into the genes, tissues and cell types involved in any disease, with the potential for informing drug development and delivery strategies.

Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8^(+) cells, CD4^(+) T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive...

A hallmark of Alzheimer's disease (AD), the most common form of dementia, is the progressive accumulation of amyloid-beta (Aβ) peptides across distinct brain regions. Anti-Aβ antibodies (Aβ-Abs) targeting specific Aβ variants are essential tools for AD research, diagnostics, and therapy. The monoclonal antibodies Aducanumab, Lecanemab, and Donanemab have recently been approved as the first disease-modifying treatments for early AD, highlighting the clinical importance of their exact binding...

Golgi fragmentation is a prominent early hallmark of neurodegenerative diseases such as Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS), yet the shared molecular mechanisms underlying this phenomenon remain poorly understood. Here we identify the E3 ubiquitin ligase ITCH as a central regulator of Golgi integrity and proteostasis. Elevated ITCH disrupts both cis- and trans-Golgi networks, dislocates lysosomal hydrolase sorting factors, and impairs maturation of hydrolases. The...

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...