This week, we've collected the latest articles in the field of Ageing and Neurodegenerative Diseases. Welcome your all to read and share articles, and follow AND journals.
Title: Tau-targeting therapy in Alzheimer’s disease: critical advances and future opportunities
Authors: Yi Guo, Song Li, Ling-Hui Zeng, Jun Tan
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by two pathological hallmark lesions: extracellular plaques composed of β-amyloid (Aβ) peptide and intracellular neurofibrillary tangles made up of highly phosphorylated tau protein. Over the past two decades, most disease-modifying therapies against AD have been developed mainly on the basis of the amyloid cascade hypothesis with a focus on Aβ. However, these agents yielded only limited benefits against disease progression, which prompts us to revitalize the long-neglected tau hypothesis. Tau protein is a microtubule-associated protein, which can stabilize microtubules, regulate microtubule assembly, and affect the morphology and growth of neuronal axons. Much more importantly, the degree of tau pathology is more closely related to cognitive decline in AD patients than that of Aβ pathology. Therefore, tau-targeting therapy seems to be a promising approach to combat AD. This review describes the research progress of tau-targeting therapy in AD, with an emphasis on immunotherapy. The current challenges and future perspectives in this field are also discussed.
Access this article: http://dx.doi.org/10.20517/and.2022.16
Title: Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome
Authors: Mathieu Bourdenx, Adrián Martín-Segura, Aurora Scrivo, Jose A Rodriguez-Navarro, Susmita Kaushik, Inmaculada Tasset, Antonio Diaz, Nadia J Storm, Qisheng Xin, Yves R Juste, Erica Stevenson, Enrique Luengo, Cristina C Clement, Se Joon Choi, Nevan J Krogan, Eugene V Mosharov, Laura Santambrogio, Fiona Grueninger, Ludovic Collin, Danielle L Swaney, David Sulzer, Evripidis Gavathiotis, Ana Maria Cuervo
Type: Research Article
Components of the proteostasis network malfunction in aging, and reduced protein quality control in neurons has been proposed to promote neurodegeneration. Here, we investigate the role of chaperone-mediated autophagy (CMA), a selective autophagy shown to degrade neurodegeneration-related proteins, in neuronal proteostasis. Using mouse models with systemic and neuronal-specific CMA blockage, we demonstrate that loss of neuronal CMA leads to altered neuronal function, selective changes in the neuronal metastable proteome, and proteotoxicity, all reminiscent of brain aging. Imposing CMA loss on a mouse model of Alzheimer's disease (AD) has synergistic negative effects on the proteome at risk of aggregation, thus increasing neuronal disease vulnerability and accelerating disease progression. Conversely, chemical enhancement of CMA ameliorates pathology in two different AD experimental mouse models. We conclude that functional CMA is essential for neuronal proteostasis through the maintenance of a subset of the proteome with a higher risk of misfolding than the general proteome.
Access this article: https://doi.org/10.1016/j.cell.2021.03.048
Title: Influence of sleep disruption on protein accumulation in neurodegenerative diseases
Authors: Xiying Wang, Rui Wang, Jiada Li
Abnormal accumulation of disease proteins in the central nervous system is a neuropathological feature in neurodegenerative disorders. Recently, a growing body of evidence has supported a role of disruption of the sleep-wake cycle in disease development, pathological changes and abnormal protein accumulation in neurodegenerative diseases, especially in Alzheimer’s disease and Parkinson’s disease. Sleep deprivation promotes abnormal accumulation of disease proteins. Interestingly, amyloid-β (Aβ) has daily oscillations in human cerebral spinal fluid (CSF) and is cleared more in sleep. Both circadian genes and circadian hormones are associated with disease protein deposition. Recently, the glymphatic pathway and meningeal lymphatics have been shown to play a critical role in Aβ clearance, which is mediated by the aquaporin (AQP-4) water channel on astrocytes. The rate of the clearance of Aβ by the glymphatic pathway is different during the sleep/wake cycle. Most importantly, circadian rhythms facilitate glymphatic clearance of solutes and Aβ in the CSF and interstitial fluid in an AQP-4-dependent manner, which further provides evidence for the involvement of circadian rhythms in disease protein clearance.
Access this article: http://dx.doi.org/10.20517/and.2021.10
Title: Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus
Authors: Sara Zocher, Rupert W Overall, Mathias Lesche, Andreas Dahl, Gerd Kempermann
Type: Research Article
The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracts age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is critical to neuronal function. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.
Access this article: https://doi.org/10.1038/s41467-021-23993-1
Title: Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells
Authors: Tapash Jay Sarkar, Marco Quarta, Shravani Mukherjee, Alex Colville, Patrick Paine, Linda Doan, Christopher M. Tran, Constance R. Chu, Steve Horvath, Lei S. Qi, Nidhi Bhutani, Thomas A. Rando & Vittorio Sebastiano
Type: Research Article
Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.
Access this article: https://doi.org/10.1038/s41467-020-15174-3