Review
Biochemistry & Molecular Biology
Paula M. Loveland, Jenny J. Yu, Leonid Churilov, Nawaf Yassi, Rosie Watson
Summary: This study reviewed inflammation investigation methods in Lewy body dementia (LBD) and identified alterations in inflammatory signals compared to individuals without neurodegenerative disease and other neurodegenerative diseases. The results suggest that both the innate and adaptive immune system contribute to inflammation associated with LBD pathology and clinical features.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Chang-Ki Oh, Nima Dolatabadi, Piotr Cieplak, Maria T. Diaz-Meco, Jorge Moscat, John P. Nolan, Tomohiro Nakamura, Stuart A. Lipton
Summary: This article investigates the mechanism by which dysregulation of autophagic pathways leads to the accumulation of abnormal proteins and damaged organdies in neurodegenerative disorders. The authors found that pathologic protein S-nitrosylation of p62 is a critical factor for autophagic inhibition and cell-to-cell spread.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Oluwanifemi Shola-Dare, Shelby Bailess, Carlos C. Flores, William M. Vanderheyden, Jason R. Gerstner
Summary: Parkinson's Disease (PD) and Gaucher Disease (GD) are genetically linked, with no effective treatment currently available. Research has shown that thiazolidinediones may help improve the neurological symptoms of these two diseases. By enhancing the function of the lysosomal-autophagy pathways, these compounds could enhance the treatment outcomes of both diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Ethan W. Hass, Zachary A. Sorrentino, Yuxing Xia, Grace M. Lloyd, John Q. Trojanowski, Stefan Prokop, Benoit Giasson
Summary: Studies demonstrate significant differences in carboxy terminal alpha Syn processing associated with pathological inclusions in different disease types, brain regions, and cell populations.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
Review
Clinical Neurology
Jon B. Toledo, Carla Abdelnour, Rimona S. Weil, Daniel Ferreira, Federico Rodriguez-Porcel, Andrea Pilotto, Kathryn A. Wyman-Chick, Michel J. Grothe, Joseph P. M. Kane, Angela Taylor, Arvid Rongve, Sonja Scholz, James B. Leverenz, Bradley F. Boeve, Dag Aarsland, Ian G. McKeith, Simon Lewis, Iracema Leroi, John P. Taylor
Summary: Dementia with Le bodies (DLB) is clinically characterized by visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. However, neuropathological studies have shown the coexistence of Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologies in DLB cases. These co-pathologies should be taken into consideration in clinical trials for DLB individuals.
ALZHEIMERS & DEMENTIA
(2023)
Review
Biochemistry & Molecular Biology
Engila Khan, Ikramul Hasan, M. Emdadul Haque
Summary: Disease modeling in non-human subjects is crucial for clinical research. Animal models are necessary to replicate the disease process and understand the etiology and pathophysiology. Parkinson's disease, with its progressive nature and various disabilities, has specific pathological hallmarks that involve misfolded protein accumulation and degeneration of neurons. Extensive research has been conducted on Parkinson's disease animal models, including pharmacological and genetic manipulation induction. This review summarizes and discusses commonly used Parkinson's disease animal model systems, as well as their applications and limitations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
George K. Tofaris
Summary: alpha-Synuclein aggregation is a critical molecular process in Parkinson's disease pathogenesis, and its nature influences the clinical heterogeneity. Alpha-synuclein assemblies need to exhibit seeding competency and toxicity for neurodegeneration to occur. It is currently unknown which alpha-synuclein assemblies are most relevant to the human condition.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Neurosciences
Leyre Basurco, Miguel Angel Abellanas, Leyre Ayerra, Enrique Conde, Rodrigo Vinueza-Gavilanes, Esther Luquin, Africa Vales, Amaya Vilas, Patxi San Martin-Uriz, Ibon Tamayo, Marta M. Alonso, Mikel Hernaez, Gloria Gonzalez-Aseguinolaza, Pedro Clavero, Elisa Mengual, Montserrat Arrasate, Sandra Hervas-Stubbs, Maria S. Aymerich
Summary: In this study, the innate immune reaction in the midbrain and striatum of Parkinson's disease was assessed. The results showed that CD11b(+) cells in the parkinsonian midbrain presented an anti-inflammatory profile, while CD11b(+) cells in the striatum showed a pro-inflammatory state. Astrocytes exhibited a pro-inflammatory fingerprint in the midbrain. The findings highlight the importance of selecting appropriate cell targets to design neuroprotective strategies in the active phase of dopaminergic degeneration.
Article
Neurosciences
Per Borghammer, Jacob Horsager, Katrine Andersen, Nathalie Van den Berge, Anna Raunio, Shigeo Murayama, Laura Parkkinen, Liisa Myllykangas
Summary: The aggregation of alpha-synuclein into inclusion bodies, known as Lewy pathology, is a key feature of Parkinson's disease and Dementia with Lewy bodies. Post mortem studies have shown that Lewy pathology follows two main distribution patterns in the brain, with some patients having pathogenic alpha-synuclein originating in the enteric nervous system and others originating inside the central nervous system.
NEUROBIOLOGY OF DISEASE
(2021)
Review
Biochemistry & Molecular Biology
Junna Hayashi, John A. Carver
Summary: This article reviews the current literature on human βS to better understand its role in homeostasis and pathology. The structure of βS is discussed, as well as its ability to act as a molecular chaperone, regulate synaptic function and other cellular pathways. The mutations associated with dementia with Lewy bodies are also explored, along with the impact of post-translational modifications on βS.
Review
Clinical Neurology
David J. Koss, Susanna Campesan, Flaviano Giorgini, Tiago F. Outeiro
Summary: Intracellular vesicular trafficking is crucial for neuronal development and function, with RAB proteins playing a key role in this process; Impairment of RAB39B is associated with intellectual disability and Parkinson's disease, as well as several LBDs; Recent studies have shown altered expression of RAB39B in various LBDs.
MOVEMENT DISORDERS
(2021)
Article
Neurosciences
Tarun N. Bhatia, Anuj S. Jamenis, Muslim Abbas, Rachel N. Clark, Kristin M. Miner, Manisha N. Chandwani, Roxanne E. Kim, William Hilinski, Lauren A. O'Donnell, Kelvin C. Luk, Yejie Shi, Xiaoming Hu, Jun Chen, Jeffrey L. Brodsky, Rehana K. Leak
Summary: Reactive microglia are observed in aging and Lewy body disorders, and resetting these cells with the CSF1R inhibitor PLX5622 may have therapeutic potential. In the PFF model of alpha-synuclein fibrils, short-term dietary exposure to PLX5622 reduced inclusion numbers and insoluble alpha-synuclein in aged males, but raised inclusion sizes in both sexes. Transient delivery of PLX5622 also improved spatial reference memory in PFF-infused aged mice.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Medicine, Research & Experimental
Qianqian Cao, Shilin Luo, Wei Yao, Youge Qu, Nanbu Wang, Jian Hong, Shigeo Murayama, Zhentao Zhang, Jiaxu Chen, Kenji Hashimoto, Qi Qi, Ji-chun Zhang
Summary: Parkinson's disease is characterized by the formation of Lewy bodies in the brain, and utilizing DNA/RNA heteroduplex oligonucleotides shows promise in reducing alpha-Syn expression to alleviate pathological changes and dopaminergic neuron degeneration in PD mouse models.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Neurosciences
Vedad Delic, Joshua H. Karp, Maynard Guzman, Gabriel R. Arismendi, Katherine J. Stalnaker, Julia A. Burton, Kathleen E. Murray, Joshua P. Stamos, Kevin D. Beck, Arpine Sokratian, Andrew B. West, Bruce A. Citron
Summary: Population studies have shown that traumatic brain injury is associated with an increased risk for Parkinson's disease. This study found that repetitive mild brain injury may create an environment conducive to Parkinson's disease pathology nucleation, but it does not accelerate the development of preexisting pathology. The findings highlight the importance of further research on the relationship between brain injury and Parkinson's disease.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2022)
Article
Neurosciences
Scott C. Vermilyea, Anne Christensen, Joyce Meints, Balvindar Singh, Hector Martell-Martinez, Md. Razaul Karim, Michael K. Lee
Summary: The role of tau in the development and progression of alpha-synucleinopathy was investigated in a transgenic mouse model. The results showed that loss of tau expression delayed the onset of motor deficits and the progression of alpha-synucleinopathy, improved neurodegeneration markers, and increased survival. In vitro experiments also demonstrated that tau removal prevented neurotoxicity caused by alpha-synuclein pathology. This study supports further investigation of tau as a potential therapeutic target for alpha-synucleinopathies.
TRANSLATIONAL NEURODEGENERATION
(2022)
Article
Clinical Neurology
Nelson Ferreira, Hjalte Gram, Zachary A. Sorrentino, Emil Gregersen, Sissel Ida Schmidt, Lasse Reimer, Cristine Betzer, Clara Perez-Gozalbo, Marjo Beltoja, Madhu Nagaraj, Jie Wang, Jan S. Nowak, Mingdong Dong, Katarina Willen, Ersoy Cholak, Kaare Bjerregaard-Andersen, Nicolas Mendez, Prakruti Rabadia, Mohammad Shahnawaz, Claudio Soto, Daniel E. Otzen, Umit Akbey, Morten Meyer, Benoit I. Giasson, Marina Romero-Ramos, Poul Henning Jensen
Summary: The discovery of a novel alpha-Synuclein strain induced by multiple system atrophy-associated protein p25 alpha indicates a distinct structure and enhanced prodegenerative properties compared to native alpha-Syn. This unique strain has a greater impact on dopamine neurons and results in a shortened lifespan and altered anatomical distribution of inclusion pathology in mice. These findings suggest that oligodendroglial protein p25 alpha plays a significant role in generating a highly aggressive alpha-Syn strain in multiple system atrophy.
ACTA NEUROPATHOLOGICA
(2021)
Article
Pathology
Anthony T. Yachnis, Jeffrey A. Golden
PEDIATRIC AND DEVELOPMENTAL PATHOLOGY
(2022)
Review
Neurosciences
Yuxing Xia, Stefan Prokop, Benoit I. Giasson
Summary: Phosphorylation is a common post-translational modification in tau protein isolated from Alzheimer's disease patients, with therapeutic approaches targeting phosphorylated tau showing promise in slowing hyperphosphorylation and aggregation. The identification and monitoring of phosphorylated tau could serve as disease-specific biomarkers, aiding in clinical diagnosis and progression monitoring.
MOLECULAR NEURODEGENERATION
(2021)
Article
Neurosciences
Grace M. Lloyd, Jess-Karan S. Dhillon, Kimberly-Marie M. Gorion, Cara Riffe, Susan E. Fromholt, Yuxing Xia, Benoit Giasson, David R. Borchelt
Summary: This study revealed novel and unexpected interplays among alpha-synuclein pathology, A beta, and neuroinflammation in mice, recapitulating the pathology of Alzheimer's disease and Lewy body dementia.
MOLECULAR NEURODEGENERATION
(2021)
Article
Oncology
Roger E. McLendon, Anthony T. Yachnis, C. Ryan Miller, Ho-Keung Ng
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2022)
Article
Clinical Neurology
Emily J. Koller, Kristen R. Ibanez, Quan Vo, Karen N. McFarland, Elsa Gonzalez De la Cruz, Lillian Zobel, Tristan Williams, Guilian Xu, Daniel Ryu, Preya Patel, Benoit Giasson, Stefan Prokop, Paramita Chakrabarty
Summary: The study reveals that different tau mutations exhibit varying degrees of synergy with A beta depending on the presence of cerebral deposits.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2022)
Review
Clinical Neurology
Jorge A. Trejo-Lopez, Anthony T. Yachnis, Stefan Prokop
Summary: Postmortem diagnosis remains central to Alzheimer's disease research, but advances in pathophysiology understanding and clinical diagnosis have shifted the perspective. In addition to the key pathological hallmarks, the diversity of accompanying pathological changes is gaining attention.
Article
Neurosciences
Tristan Williams, Alejandra Jolie Ruiz, Angelica Maria Ruiz, Quan Vo, Wangchen Tsering, Guilian Xu, Karen McFarland, Benoit Giasson, Patrick Sullivan, David R. Borchelt, Paramita Chakrabarty
Summary: APOE isoforms differentially regulate the burden of Alzheimer's disease-associated neuropathologies, especially phosphorylated tau pathology. Among them, the APOE3 genotype in mice is more prone to accumulate tau protein and exhibit microglial reactions, with a stronger response to K18-tau infection, which might be a contributing factor to the increased risk of Alzheimer's disease. Additionally, we did not observe neurofibrillary tau tangles induced by APOE homozygous mice in our study.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2022)
Article
Biology
Yuxing Xia, Stefan Prokop, Brach M. Bell, Kimberly-Marie M. Gorion, Cara L. Croft, Lith Nasif, Guilian Xu, Cara J. Riffe, Alyssa N. Manaois, Kevin H. Strang, Stephan S. Quintin, Giavanna Paterno, Malu Gamez Tansey, David R. Borchelt, Todd E. Golde, Benoit Giasson
Summary: This study presents a transgenic mouse model with predictable progression of pathogenic tau protein, providing insights into tau pathology in neurodegenerative diseases.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Elsa Gonzalez De la Cruz, Quan Vo, Katie Moon, Karen N. McFarland, Mary Weinrich, Tristan Williams, Benoit Giasson, Paramita Chakrabarty
Summary: MHCII molecules play a key role in the cellular immune response to alpha-synuclein, and this immune response may affect the transmission of alpha-syn seeds from the periphery to the CNS. Deficiency in MhcII accelerates the appearance of alpha-syn pathology and shortens the lifespan in PFF-seeded M83 mice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Editorial Material
Neurosciences
Yuxing Xia
JOURNAL OF NEUROSCIENCE
(2022)
Article
Clinical Neurology
Kristen R. Ibanez, Karen N. McFarland, Jennifer Phillips, Mariet Allen, Christian B. Lessard, Lillian Zobel, Elsa Gonzalez De la Cruz, Shivani Shah, Quan Vo, Xue Wang, Zachary Quicksall, Daniel Ryu, Cory Funk, Nilufer Ertekin-Taner, Stefan Prokop, Todd E. Golde, Paramita Chakrabarty
Summary: This study investigates the impact of the loss of function of Abi3-Gngt2 gene on the neuropathological hallmarks of AD, amyloid beta plaques, and tau pathology. The research provides insights into the role of inflammatory gliosis in AD and highlights the unpredictability of targeting immune pathways in AD.
ALZHEIMERS RESEARCH & THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Yuxing Xia, Brach M. M. Bell, Benoit I. I. Giasson
Summary: Alzheimer's disease and frontotemporal dementia are tauopathies characterized by toxic tau aggregates in the brain. Tau methylation, which involves post-translational modifications of tau protein, has been implicated in tau pathomechanisms. In this study, tau methylmimetics were used to model the effects of tau methylation, showing impaired microtubule binding and enhanced tau aggregation. These findings suggest that tau methylation could be a potential therapeutic target for the treatment of tauopathies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Yuxing Xia, Brach M. M. Bell, Justin D. D. Kim, Benoit I. I. Giasson
Summary: Tauopathies are neurodegenerative diseases characterized by the formation of tau brain aggregates. Imbalance of 3R and 4R tau isoforms is a contributing factor in the development of these diseases. The S356T tau mutation shows unique prion-like seeded aggregation, forming extensive Thioflavin positive aggregates. This finding will contribute to the understanding of diverse presentations of different tauopathies.
FRONTIERS IN NEUROSCIENCE
(2023)
Review
Clinical Neurology
Karen N. McFarland, Paramita Chakrabarty
Summary: Immune activation is associated with the development of proteinopathy in the brains of Alzheimer's dementia patients. There is accumulating evidence that microglial activation is not simply a reactive process to the proteinopathy, but a dynamic evolving process that regulates brain organ health. While immune activation can be beneficial under certain circumstances, chronic activation leads to neurodegeneration. A deeper understanding of the relationship between microglial functional states and brain organ health may lead to new interventions and therapies for Alzheimer's disease.