Pasquale D'Acunzo, Elentina K Argyrousi, Jonathan M Ungania, Yohan Kim, Steven DeRosa, Monika Pawlik, Chris N Goulbourne, Ottavio Arancio, Efrat Levy
BACKGROUND: Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer's disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain...
April 14, 2024: Molecular Neurodegeneration
Luuk E de Vries, Inge Huitinga, Helmut W Kessels, Dick F Swaab, Joost Verhaagen
Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer's Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience and has evolved into a widely debated concept. External factors such as cognitive stimulation are associated with resilience to AD, but the exact cellular and molecular underpinnings are not completely understood. In this review, we discuss the current definitions used in the field, highlight the translational approaches used to investigate resilience to AD and summarize the underlying cellular and molecular substrates of resilience that have been derived from human and animal studies, which have received more and more attention in the last few years...
April 8, 2024: Molecular Neurodegeneration
María Llorián-Salvador, Alerie G de Fuente, Christopher E McMurran, Amy Dashwood, James Dooley, Adrian Liston, Rosana Penalva, Yvonne Dombrowski, Alan W Stitt, Denise C Fitzgerald
BACKGROUND: Ageing is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown...
April 5, 2024: Molecular Neurodegeneration
Marie-France Dorion, Diana Casas, Irina Shlaifer, Moein Yaqubi, Peter Fleming, Nathan Karpilovsky, Carol X-Q Chen, Michael Nicouleau, Valerio E C Piscopo, Emma J MacDougall, Aeshah Alluli, Taylor M Goldsmith, Alexandria Schneider, Samuel Dorion, Nathalia Aprahamian, Adam MacDonald, Rhalena A Thomas, Roy W R Dudley, Jeffrey A Hall, Edward A Fon, Jack P Antel, Jo Anne Stratton, Thomas M Durcan, Roberta La Piana, Luke M Healy
BACKGROUND: Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R. METHODS: Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c...
April 5, 2024: Molecular Neurodegeneration
Guy C Brown, Michael T Heneka
Lipopolysaccharide (LPS) constitutes much of the surface of Gram-negative bacteria, and if LPS enters the human body or brain can induce inflammation and act as an endotoxin. We outline the hypothesis here that LPS may contribute to the pathophysiology of Alzheimer's disease (AD) via peripheral infections or gut dysfunction elevating LPS levels in blood and brain, which promotes: amyloid pathology, tau pathology and microglial activation, contributing to the neurodegeneration of AD. The evidence supporting this hypothesis includes: i) blood and brain levels of LPS are elevated in AD patients, ii) AD risk factors increase LPS levels or response, iii) LPS induces Aβ expression, aggregation, inflammation and neurotoxicity, iv) LPS induces TAU phosphorylation, aggregation and spreading, v) LPS induces microglial priming, activation and neurotoxicity, and vi) blood LPS induces loss of synapses, neurons and memory in AD mouse models, and cognitive dysfunction in humans...
April 1, 2024: Molecular Neurodegeneration
Anna Calliari, Lillian M Daughrity, Ellen A Albagli, Paula Castellanos Otero, Mei Yue, Karen Jansen-West, Naeyma N Islam, Thomas Caulfield, Bailey Rawlinson, Michael DeTure, Casey Cook, Neill R Graff-Radford, Gregory S Day, Bradley F Boeve, David S Knopman, Ronald C Petersen, Keith A Josephs, Björn Oskarsson, Aaron D Gitler, Dennis W Dickson, Tania F Gendron, Mercedes Prudencio, Michael E Ward, Yong-Jie Zhang, Leonard Petrucelli
This letter demonstrates the potential of novel cryptic proteins resulting from TAR DNA-binding protein 43 (TDP-43) dysfunction as markers of TDP-43 pathology in neurodegenerative diseases.
March 27, 2024: Molecular Neurodegeneration
Araks Martirosyan, Rizwan Ansari, Francisco Pestana, Katja Hebestreit, Hayk Gasparyan, Razmik Aleksanyan, Silvia Hnatova, Suresh Poovathingal, Catherine Marneffe, Dietmar R Thal, Andrew Kottick, Victor J Hanson-Smith, Sebastian Guelfi, William Plumbly, T Grant Belgard, Emmanouil Metzakopian, Matthew G Holt
No abstract text is available yet for this article.
March 25, 2024: Molecular Neurodegeneration
Qingyi Ma, Zhen Zhao, Abhay P Sagare, Yingxi Wu, Min Wang, Nelly Chuqui Owens, Philip B Verghese, Joachim Herz, David M Holtzman, Berislav V Zlokovic
No abstract text is available yet for this article.
March 22, 2024: Molecular Neurodegeneration
Rebecca Z Fan, Carolina Sportelli, Yanhao Lai, Said S Salehe, Jennifer R Pinnell, Harry J Brown, Jason R Richardson, Shouqing Luo, Kim Tieu
BACKGROUND: Dynamin-related protein 1 (Drp1) plays a critical role in mitochondrial dynamics. Partial inhibition of this protein is protective in experimental models of neurological disorders such as Parkinson's disease and Alzheimer's disease. The protective mechanism has been attributed primarily to improved mitochondrial function. However, the observations that Drp1 inhibition reduces protein aggregation in such neurological disorders suggest the involvement of autophagy. To investigate this potential novel protective mechanism of Drp1 inhibition, a model with impaired autophagy without mitochondrial involvement is needed...
March 19, 2024: Molecular Neurodegeneration
Hyo Jung Shin, In Soo Kim, Seung Gyu Choi, Kayoung Lee, Hyewon Park, Juhee Shin, Dayoung Kim, Jaewon Beom, Yoon Young Yi, Deepak Prasad Gupta, Gyun Jee Song, Won-Suk Chung, C Justin Lee, Dong Woon Kim
Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance...
March 16, 2024: Molecular Neurodegeneration
Jordy Sepulveda, Jennifer Yejean Kim, Joseph Binder, Stefano Vicini, G William Rebeck
Microglia are highly dynamic cells that play a critical role in tissue homeostasis through the surveillance of brain parenchyma and response to cues associated with damage. Aging and APOE4 genotype are the strongest risk factors for Alzheimer's disease (AD), but how they affect microglial dynamics remains unclear. Using ex vivo confocal microscopy, we analyzed microglial dynamic behaviors in the entorhinal cortex (EC) and hippocampus CA1 of 6-, 12-, and 21-month-old mice APOE3 or APOE4 knock-in mice expressing GFP under the CX3CR1 promoter...
March 11, 2024: Molecular Neurodegeneration
Michael Z Zhong, Thomas Peng, Mariana Lemos Duarte, Minghui Wang, Dongming Cai
Alzheimer's disease (AD) is the most common neurodegenerative disease in the United States (US). Animal models, specifically mouse models have been developed to better elucidate disease mechanisms and test therapeutic strategies for AD. A large portion of effort in the field was focused on developing transgenic (Tg) mouse models through over-expression of genetic mutations associated with familial AD (FAD) patients. Newer generations of mouse models through knock-in (KI)/knock-out (KO) or CRISPR gene editing technologies, have been developed for both familial and sporadic AD risk genes with the hope to more accurately model proteinopathies without over-expression of human AD genes in mouse brains...
March 11, 2024: Molecular Neurodegeneration
Ilaria Gregorio, Loris Russo, Enrica Torretta, Pietro Barbacini, Gabriella Contarini, Giada Pacinelli, Dario Bizzotto, Manuela Moriggi, Paola Braghetta, Francesco Papaleo, Cecilia Gelfi, Enrico Moro, Matilde Cescon
BACKGROUND: Mutations in the β-glucocerebrosidase (GBA1) gene do cause the lysosomal storage Gaucher disease (GD) and are among the most frequent genetic risk factors for Parkinson's disease (PD). So far, studies on both neuronopathic GD and PD primarily focused on neuronal manifestations, besides the evaluation of microglial and astrocyte implication. White matter alterations were described in the central nervous system of paediatric type 1 GD patients and were suggested to sustain or even play a role in the PD process, although the contribution of oligodendrocytes has been so far scarcely investigated...
March 7, 2024: Molecular Neurodegeneration
Jun Yup Lee, Dylan J Harney, Jonathan D Teo, John B Kwok, Greg T Sutherland, Mark Larance, Anthony S Don
No abstract text is available yet for this article.
February 27, 2024: Molecular Neurodegeneration
Dillon J Rinauro, Fabrizio Chiti, Michele Vendruscolo, Ryan Limbocker
The conversion of native peptides and proteins into amyloid aggregates is a hallmark of over 50 human disorders, including Alzheimer's and Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the amyloid formation process as the primary cytotoxic agents in many of these devastating conditions. In this review, we analyze the processes by which oligomers are formed, their structures, physicochemical properties, population dynamics, and the mechanisms of their cytotoxicity...
February 20, 2024: Molecular Neurodegeneration
Megan E Bosch, Hemraj B Dodiya, Julia Michalkiewicz, Choonghee Lee, Shabana M Shaik, Ian Q Weigle, Can Zhang, Jack Osborn, Aishwarya Nambiar, Priyam Patel, Samira Parhizkar, Xiaoqiong Zhang, Marie L Laury, Prasenjit Mondal, Ashley Gomm, Matthew John Schipma, Dania Mallah, Oleg Butovsky, Eugene B Chang, Rudolph E Tanzi, Jack A Gilbert, David M Holtzman, Sangram S Sisodia
It has recently become well-established that there is a connection between Alzheimer's disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels...
February 17, 2024: Molecular Neurodegeneration
Juan Lantero-Rodriguez, Gemma Salvadó, Anniina Snellman, Laia Montoliu-Gaya, Wagner S Brum, Andrea L Benedet, Niklas Mattsson-Carlgren, Pontus Tideman, Shorena Janelidze, Sebastian Palmqvist, Erik Stomrud, Nicholas J Ashton, Henrik Zetterberg, Kaj Blennow, Oskar Hansson
BACKGROUND: Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer's disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain...
February 17, 2024: Molecular Neurodegeneration
Grace M Lloyd, Jess-Karan S Dhillon, Kimberly-Marie M Gorion, Cara Riffe, Susan E Fromholt, Yuxing Xia, Benoit I Giasson, David R Borchelt
No abstract text is available yet for this article.
February 16, 2024: Molecular Neurodegeneration
Dan Hu, Howard L Weiner
No abstract text is available yet for this article.
February 14, 2024: Molecular Neurodegeneration
Sára Mravinacová, Vilma Alanko, Sofia Bergström, Claire Bridel, Yolande Pijnenburg, Göran Hagman, Miia Kivipelto, Charlotte Teunissen, Peter Nilsson, Anna Matton, Anna Månberg
BACKGROUND: Amyloid and tau aggregates are considered to cause neurodegeneration and consequently cognitive decline in individuals with Alzheimer's disease (AD). Here, we explore the potential of cerebrospinal fluid (CSF) proteins to reflect AD pathology and cognitive decline, aiming to identify potential biomarkers for monitoring outcomes of disease-modifying therapies targeting these aggregates. METHOD: We used a multiplex antibody-based suspension bead array to measure the levels of 49 proteins in CSF from the Swedish GEDOC memory clinic cohort at the Karolinska University Hospital...
February 13, 2024: Molecular Neurodegeneration
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