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Organelle interactome disruption: The systemic pathological mechanisms and therapeutic prospects of mitochondria-lysosome-ER crosstalk in Alzheimer's disease

1 week 1 day ago
The traditional pathological framework of Alzheimer's disease (AD) primarily focuses on the accumulation of β-amyloid (Aβ) and tau proteins. However, therapeutic strategies targeting these molecules have repeatedly encountered setbacks in clinical translation. Recent studies have progressively revealed that the dynamic interaction network among intracellular organelles plays a central role in the pathogenesis of AD. This systematic review examines the independent dysfunctions of three key...
Liping Xing

TNMD BRICHOS domain attenuates tau pathology and memory deficits in a mouse model of tauopathy

1 week 1 day ago
The aberrant aggregation of tau leads to loss of its physiological functions and gain of toxic functions, and plays a crucial role in the pathogenesis of tauopathies including Alzheimer's disease (AD). Targeting tau aggregation is considered a promising strategy for treating tauopathies. The BRICHOS family consists of a variety of proteins containing the BRICHOS domain. Certain endogenous BRICHOS domains may inhibit the pathological aggregation of disease-associated proteins. However, the...
Dandan Su

Type I interferon drives T cell responses to amyloid beta in the central nervous system

1 week 1 day ago
Amyloid beta (Aβ) plaque deposition in the central nervous system (CNS) is a hallmark of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), triggering robust innate immune responses. However, the role of the adaptive immune system remains less well understood. Here we show the immune microenvironment dynamics in APP23 transgenic (APP23-tg) mice modelling CNS amyloid pathology, using single-cell transcriptomics. We observed a marked increase in T-cell populations during late disease...
Julius J Michel

Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease

1 week 1 day ago
The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. Here we show that dopamine neurons projecting their axons to the lateral entorhinal cortex (LEC), critical...
Tatsuki Nakagawa

AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models

1 week 1 day ago
GM2 gangliosidoses, including Tay-Sachs (TSD) and Sandhoff (SD) diseases, are lysosomal storage disorders with neurological manifestations caused by the excessive accumulation of GM2 ganglioside due to the deficiency of the β-hexosaminidase A (HexA). Although gene therapy approaches are underway, concerns regarding efficacy and safety remain. Here, we evaluate a tyrosine-mutant adeno-associated virus serotype 9 (AAV9/3) vector encoding modified HEXB (modHEXB) wherein nine amino acid residues are...
Keisuke Kitakaze

The long-lived immune system of centenarians

1 week 1 day ago
Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-related diseases or postponing their onset. Despite their advanced age, many centenarians show relatively preserved immune function and resistance to conditions linked to immunosenescence and chronic low-grade inflammation (inflammageing). These features are especially pronounced in...
Abel Plaza-Florido

Subclonal beta-catenin/YAP signaling heterogeneity accelerates ovarian cancer metastasis through a senescence-associated secretory phenotype

1 week 1 day ago
Intratumoral heterogeneity in metastatic cancers complicates effective treatment, as distinct tumor subclones display varying drug sensitivities and metastatic capabilities, interacting through mechanisms that remain poorly understood. In this study, we utilized an isogenic ovarian cancer cell pair distinguished by differential β-catenin signaling: non-metastatic (NM) cells with low β-catenin and highly metastatic (HM) cells with elevated β-catenin signaling. Co-engrafting NM and HM cells...
Sally K Y To

Reduction of glycation stress as a geroscience intervention: protocol for a pilot RCT in postmenopausal women

1 week 1 day ago
Advanced glycation end products (AGEs) drive metabolic dysfunction, inflammation, and age-related disease, and their accumulation accelerates after menopause. Preclinical studies show that GLYLO, a five-compound glycation-lowering formulation (alpha-lipoic acid, nicotinamide, pyridoxine, benfotiamine, and piperine), reduces AGE burden and improves metabolic health, but its translational relevance in humans is unknown. The Glycation Reduction and Aging: a Clinical Evaluation (GRACE) trial is a...
Vineeta Tanwar