Alzheimer & Parkinson

Yu and colleagues¹ demonstrate that α-synuclein pathology within the dorsal motor nucleus of the vagus (DMV) compromises neuronal excitability and drives Parkinson's disease-related gastrointestinal dysmotility through alteration of a fundamental DMV-gut circuit. Electroacupuncture reactivates this circuit ameliorating this functional deficit.

This year's Lasker~Bloomberg Public Service Award honors the singular achievement of Michael J. Fox, who has devoted much of his life to a philanthropic effort to conquer Parkinson's Disease (PD), a progressive neurodegenerative disorder that afflicts many millions of patients world-wide. Just a few years after his diagnosis of PD at the tender age of 29, Fox pivoted in part from his enormous success in acting [leading roles in the Back to the Future trilogy (1985-1989) and in the hit National...

Bone marrow-derived macrophages were shown to play an important role in coping with Alzheimer's disease (AD). Boosting their spontaneous recruitment reduces inflammation and disease pathology and slows cognitive decline in mouse models of amyloidosis. However, the factors limiting their spontaneous homing to the diseased brain remain unclear. In this study, we discovered that monocyte development is impaired in mouse models and in patients. In the 5×FAD mouse model, monocyte differentiation was...

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Primary cultures from fetal or postnatal rodent brain are widely used to study alpha-synuclein (aSyn)-associated mechanisms but poorly reflect age-dependent neurodegenerative processes. We established primary whole-brain cultures from adult Thy1-aSyn (Line 61) mice overexpressing human aSyn and compared them with postnatal and wild-type cultures. Cultures were maintained for 21 days and characterized by electrophysiology, immunohistochemistry, gene expression analysis, and protein biochemistry....

Antibody-based immunotherapy targeting amyloid-β (Aβ) is a promising approach for Alzheimer's disease (AD). However, its efficacy is limited by rapid hepatic sequestration, complement activation, and liver dysfunction. In this study, we synthesized low-immunogenic 450-nm functionalized mesoporous silica nanoparticles (PEG-MSN-1F12) by conjugating the anti-Aβ(42) monoclonal antibody 1F12 to polyethylene glycol-modified mesoporous silica nanoparticles to address these challenges. In APP/PS1 mice,...

Dopaminergic neurons constitute a heterogeneous neuronal system that regulates diverse brain functions, whereas distinct dopaminergic neuronal subpopulations exhibit unique intrinsic biological properties, selective vulnerability, and disease-specific pathological trajectories across neurodegenerative disorders. Parkinson's disease (PD) is characterized by the progressive degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, whereas Alzheimer's disease (AD) predominantly...

CONCLUSION: Translational development faces several barriers, including poor blood-brain barrier (BBB) penetration, off-target neurotoxicity, uncharacterised long-term safety and limited generalisability from APP/PS1 models lacking tauopathy. All MERCS-targeted and senolytic combinatorial strategies discussed herein represent prospective pre-clinical research directions rather than mature clinical therapeutic approaches. We propose an experimental roadmap based on conditional knockouts,...

Proteins exist as diverse proteoforms resulting from a combination of genetic variation, alternative splicing and post-translational modifications. Current methods struggle to capture this complexity at the single-molecule level. Here we introduce Iterative Mapping of proteoforms, a method that enables massively parallel interrogation of millions to billions of single-protein molecules through iterative probing with fluorescently labeled antibodies. We applied Iterative Mapping to tau, a key...

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Conventional downstream interventions targeting β-amyloid (Aβ) and tau proteins have repeatedly failed in clinical practice, and mitochondrial functional decline has been identified as the core upstream driver of AD pathogenesis. Focusing on the mitochondrial functional network as the core target, this paper systematically dissects the key molecular mechanisms of mitochondrial dysfunction during AD progression,...

The gut microbiome acts as a primary regulator of host homeostasis, influencing the entire body through bidirectional communication along the gut-brain axis (GBA). Dysbiosis, which is defined as a state of microbial imbalance involving alterations in community composition and function, can disrupt the synthesis of important microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), bile acids and neurotransmitter precursors. This can lead to impaired essential host signalling...

Both serum serotonin and cardiovascular-risk (CVR) burden are implicated in Alzheimer's disease (AD)-related vascular and neurodegenerative processes, yet their interrelationship across the AD continuum remains unclear. This cross-sectional study examined whether serum serotonin was associated with three complementary measures of CVR burden across the AD continuum and according to CSF amyloid status in 428 participants (138 cognitively normal [CN] individuals, 206 participants with mild...

Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains...

Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8^(+) T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8^(+) T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen...

Plasma pTau217 is a leading biomarker for Alzheimer's disease, but evidence from genetically admixed populations in low- and middle-income countries remains limited. We evaluated the diagnostic performance of pTau217 and pTau217/Aβ42 measured using Simoa technology in memory-clinic cohorts from Brazil (Cog-Aging-Study, n = 353) and Argentina (GeNED.ar, n = 134). Here we show that both biomarkers accurately identified cerebrospinal fluid (CSF)-defined amyloid pathology in Cog-Aging-Study-Brazil...

BACKGROUND: As individuals with Down syndrome age, they face high risks of Alzheimer's disease and epilepsy. With symptomatic Alzheimer's disease, late-onset myoclonic epilepsy in Down syndrome (LOMEDS) often emerges. We aimed to examine how epilepsy develops in Down syndrome, its timing relative to Alzheimer's disease symptom onset, and its effect on prognosis.

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Microglia are the resident macrophages of the central nervous system¹. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult haematopoiesis^(2-4). The origins of human microglia are less clear, but recent evidence suggests that bone-marrow-derived cells contribute to the human microglial pool in certain individuals^(5-9). Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of...

Parkinson's disease (PD) is a neurodegenerative disorder involving a neuroinflammatory response, the cause of which remains unclear. Transposable elements (TEs) have been linked to inflammation, but their potential role in PD remains unexplored. Using bulk- and single-nuclei RNA-seq of postmortem brain tissue from four brain regions, we studied TE transcription and its correlation with PD neuroinflammation. Over a thousand TEs, including LINE-1 s and ERVs, were expressed in a cell type- and...

Tau pathology closely tracks neuronal loss in Alzheimer's disease, but how phosphorylated tau becomes lethal has remained unclear. Chen et al. identify a dual-hit mechanism: glucose hypometabolism removes a protective A20-mediated brake on necroptosis while phosphorylated tau scaffolds RIPK1 activation, driving tau-associated neuronal death.¹.