Stephan A Müller, Merav D Shmueli, Xiao Feng, Johanna Tüshaus, Neele Schumacher, Ryan Clark, Brad E Smith, An Chi, Stefan Rose-John, Matthew E Kennedy, Stefan F Lichtenthaler
BACKGROUND: The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates. METHODS: To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. RESULTS: Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate...
February 21, 2023: Molecular Neurodegeneration
Kristine M Tran, Shimako Kawauchi, Enikö A Kramár, Narges Rezaie, Heidi Yahan Liang, Jasmine S Sakr, Angela Gomez-Arboledas, Miguel A Arreola, Celia da Cunha, Jimmy Phan, Shuling Wang, Sherilyn Collins, Amber Walker, Kai-Xuan Shi, Jonathan Neumann, Ghassan Filimban, Zechuan Shi, Giedre Milinkeviciute, Dominic I Javonillo, Katelynn Tran, Magdalena Gantuz, Stefania Forner, Vivek Swarup, Andrea J Tenner, Frank M LaFerla, Marcelo A Wood, Ali Mortazavi, Grant R MacGregor, Kim N Green
BACKGROUND: The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current Trem2 R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2R47H NSS (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products...
February 17, 2023: Molecular Neurodegeneration
Ahmed Haider, Nehal H Elghazawy, Alyaa Dawoud, Catherine Gebhard, Thomas Wichmann, Wolfgang Sippl, Marius Hoener, Ernest Arenas, Steven H Liang
Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects elderly people and constitutes a major source of disability worldwide. Notably, the neuropathological hallmarks of PD include nigrostriatal loss and the formation of intracellular inclusion bodies containing misfolded α-synuclein protein aggregates. Cardinal motor symptoms, which include tremor, rigidity and bradykinesia, can effectively be managed with dopaminergic therapy for years following symptom onset. Nonetheless, patients ultimately develop symptoms that no longer fully respond to dopaminergic treatment...
February 10, 2023: Molecular Neurodegeneration
Kathrin Wenger, Arthur Viode, Christoph N Schlaffner, Patrick van Zalm, Long Cheng, Tammy Dellovade, Xavier Langlois, Anthony Bannon, Rui Chang, Theresa R Connors, Derek Oakley, Bernhard Renard, Juri Rappsilber, Bradley Hyman, Hanno Steen, Judith A Steen
BACKGROUND: Mouse models that overexpress human mutant Tau (P301S and P301L) are commonly used in preclinical studies of Alzheimer's Disease (AD) and while several drugs showed therapeutic effects in these mice, they were ineffective in humans. This leads to the question to which extent the murine models reflect human Tau pathology on the molecular level. METHODS: We isolated insoluble, aggregated Tau species from two common AD mouse models during different stages of disease and characterized the modification landscape of the aggregated Tau using targeted and untargeted mass spectrometry-based proteomics...
February 2, 2023: Molecular Neurodegeneration
Sidhanth Chandra, Sangram S Sisodia, Robert J Vassar
Alzheimer's disease (AD), the most common cause of dementia, results in a sustained decline in cognition. There are currently few effective disease modifying therapies for AD, but insights into the mechanisms that mediate the onset and progression of disease may lead to new, effective therapeutic strategies. Amyloid beta oligomers and plaques, tau aggregates, and neuroinflammation play a critical role in neurodegeneration and impact clinical AD progression. The upstream modulators of these pathological features have not been fully clarified, but recent evidence indicates that the gut microbiome (GMB) may have an influence on these features and therefore may influence AD progression in human patients...
February 1, 2023: Molecular Neurodegeneration
Wenhui Qiao, Yixing Chen, Jun Zhong, Benjamin J Madden, Cristine M Charlesworth, Yuka A Martens, Chia-Chen Liu, Joshua Knight, Tadafumi C Ikezu, Kurti Aishe, Yiyang Zhu, Axel Meneses, Cassandra L Rosenberg, Lindsey A Kuchenbecker, Lucy K Vanmaele, Fuyao Li, Kai Chen, Francis Shue, Maxwell V Dacquel, John Fryer, Akhilesh Pandey, Na Zhao, Guojun Bu
BACKGROUND: The rare p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) was found to increase Alzheimer's disease (AD) risk. This mutation is located at the cleavage site of TREM2 extracellular domain. Ectopic expression of TREM2-H157Y in HEK293 cells resulted in increased TREM2 shedding. However, the physiological outcomes of the TREM2 H157Y mutation remain unknown in the absence and presence of AD related pathologies. METHODS: We generated a novel Trem2 H157Y knock-in mouse model through CRISPR/Cas9 technology and investigated the effects of Trem2 H157Y on TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathologies by conducting biochemical assays, targeted mass spectrometry analysis of TREM2, hippocampal electrophysiology, immunofluorescent staining, in vivo micro-dialysis, and cortical bulk RNA sequencing...
January 31, 2023: Molecular Neurodegeneration
Kassandra Kisler, Abhay P Sagare, Divna Lazic, Sam Bazzi, Erica Lawson, Ching-Ju Hsu, Yaoming Wang, Anita Ramanathan, Amy R Nelson, Zhen Zhao, Berislav V Zlokovic
BACKGROUND: PICALM is one of the most significant susceptibility factors for Alzheimer's disease (AD). In humans and mice, PICALM is highly expressed in brain endothelium. PICALM endothelial levels are reduced in AD brains. PICALM controls several steps in Aβ transcytosis across the blood-brain barrier (BBB). Its loss from brain endothelium in mice diminishes Aβ clearance at the BBB, which worsens Aβ pathology, but is reversible by endothelial PICALM re-expression. Thus, increasing PICALM at the BBB holds potential to slow down development of Aβ pathology...
January 27, 2023: Molecular Neurodegeneration
Guojun Bu, Hui Zheng
No abstract text is available yet for this article.
January 26, 2023: Molecular Neurodegeneration
Katarina Stoklund Dittlau, Lisanne Terrie, Pieter Baatsen, Axelle Kerstens, Lim De Swert, Rekin's Janky, Nikky Corthout, Pegah Masrori, Philip Van Damme, Poul Hyttel, Morten Meyer, Lieven Thorrez, Kristine Freude, Ludo Van Den Bosch
BACKGROUND: Astrocytes play a crucial, yet not fully elucidated role in the selective motor neuron pathology in amyotrophic lateral sclerosis (ALS). Among other responsibilities, astrocytes provide important neuronal homeostatic support, however this function is highly compromised in ALS. The establishment of fully human coculture systems can be used to further study the underlying mechanisms of the dysfunctional intercellular interplay, and has the potential to provide a platform for revealing novel therapeutic entry points...
January 18, 2023: Molecular Neurodegeneration
Evan Udine, Angita Jain, Marka van Blitterswijk
Amyotrophic lateral sclerosis (ALS) is caused by upper and lower motor neuron loss and has a fairly rapid disease progression, leading to fatality in an average of 2-5 years after symptom onset. Numerous genes have been implicated in this disease; however, many cases remain unexplained. Several technologies are being used to identify regions of interest and investigate candidate genes. Initial approaches to detect ALS genes include, among others, linkage analysis, Sanger sequencing, and genome-wide association studies...
January 13, 2023: Molecular Neurodegeneration
Zhi-Hao Liu, Yan-Jiang Wang, Xian-Le Bu
No abstract text is available yet for this article.
January 11, 2023: Molecular Neurodegeneration
Stephanie R Oatman, Joseph S Reddy, Zachary Quicksall, Minerva M Carrasquillo, Xue Wang, Chia-Chen Liu, Yu Yamazaki, Thuy T Nguyen, Kimberly Malphrus, Michael Heckman, Kristi Biswas, Kwangsik Nho, Matthew Baker, Yuka A Martens, Na Zhao, Jun Pyo Kim, Shannon L Risacher, Rosa Rademakers, Andrew J Saykin, Michael DeTure, Melissa E Murray, Takahisa Kanekiyo, Dennis W Dickson, Guojun Bu, Mariet Allen, Nilüfer Ertekin-Taner
BACKGROUND: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aβ40, Aβ42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. METHODS: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency...
January 7, 2023: Molecular Neurodegeneration
Christina B Young, Emily Johns, Gabriel Kennedy, Michael E Belloy, Philip S Insel, Michael D Greicius, Reisa A Sperling, Keith A Johnson, Kathleen L Poston, Elizabeth C Mormino
BACKGROUND: APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Aβ+) remains unclear. METHODS: We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies...
January 4, 2023: Molecular Neurodegeneration
Melissa E Murray, Christina M Moloney, Naomi Kouri, Jeremy A Syrjanen, Billie J Matchett, Darren M Rothberg, Jessica F Tranovich, Tiffany N Hicks Sirmans, Heather J Wiste, Baayla D C Boon, Aivi T Nguyen, R Ross Reichard, Dennis W Dickson, Val J Lowe, Jeffrey L Dage, Ronald C Petersen, Clifford R Jack, David S Knopman, Prashanthi Vemuri, Jonathan Graff-Radford, Michelle M Mielke
BACKGROUND: Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer's disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes. METHODS: We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death...
December 27, 2022: Molecular Neurodegeneration
Jinchao Hou, Yun Chen, Gary Grajales-Reyes, Marco Colonna
Microglia are central players in brain innate immunity and have been the subject of extensive research in Alzheimer's disease (AD). In this review, we aim to summarize the genetic and functional discoveries that have advanced our understanding of microglia reactivity to AD pathology. Given the heightened AD risk posed by rare variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2), we will focus on the studies addressing the impact of this receptor on microglia responses to amyloid plaques, tauopathy and demyelination pathologies in mouse and human...
December 23, 2022: Molecular Neurodegeneration
Dong Won Kim, Kevin J Tu, Alice Wei, Ashley J Lau, Anabel Gonzalez-Gil, Tianyu Cao, Kerstin Braunstein, Jonathan P Ling, Juan C Troncoso, Philip C Wong, Seth Blackshaw, Ronald L Schnaar, Tong Li
BACKGROUND: Amongst risk alleles associated with late-onset Alzheimer's disease (AD), those that converged on the regulation of microglia activity have emerged as central to disease progression. Yet, how canonical amyloid-β (Aβ) and tau pathologies regulate microglia subtypes during the progression of AD remains poorly understood. METHODS: We use single-cell RNA-sequencing to profile microglia subtypes from mice exhibiting both Aβ and tau pathologies across disease progression...
December 17, 2022: Molecular Neurodegeneration
Sameera Zia, Brady P Hammond, Martin Zirngibl, Anastasia Sizov, Charbel S Baaklini, Sharmistha P Panda, Madelene F S Ho, Kelly V Lee, Apurba Mainali, Mena K Burr, Sioned Williams, Andrew V Caprariello, Christopher Power, Thomas Simmen, Bradley J Kerr, Jason R Plemel
BACKGROUND: Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia respond and regulate demyelination is not fully understood. METHODS: To understand how microglia respond during demyelination, we fed mice cuprizone-a potent demyelinating agent-and assessed the dynamics of genetically fate-mapped microglia. We then used single-cell RNA sequencing to identify and track the microglial subpopulations that arise during demyelination...
December 13, 2022: Molecular Neurodegeneration
Johan Gobom, Andréa L Benedet, Niklas Mattsson-Carlgren, Laia Montoliu-Gaya, Nina Schultz, Nicholas J Ashton, Shorena Janelidze, Stijn Servaes, Mathias Sauer, Tharick A Pascoal, Thomas K Karikari, Juan Lantero-Rodriguez, Gunnar Brinkmalm, Henrik Zetterberg, Oskar Hansson, Pedro Rosa-Neto, Kaj Blennow
BACKGROUND: Alzheimer's disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology. Current immunoassays measure pTau epitopes separately and may capture phosphorylated tau fragments of different length depending on the non-pTau antibody used in the assay sandwich pair, which bias the measurement...
December 12, 2022: Molecular Neurodegeneration
Bilal Khalil, Deepak Chhangani, Melissa C Wren, Courtney L Smith, Jannifer H Lee, Xingli Li, Christian Puttinger, Chih-Wei Tsai, Gael Fortin, Dmytro Morderer, Junli Gao, Feilin Liu, Chun Kim Lim, Jingjiao Chen, Ching-Chieh Chou, Cara L Croft, Amanda M Gleixner, Christopher J Donnelly, Todd E Golde, Leonard Petrucelli, Björn Oskarsson, Dennis W Dickson, Ke Zhang, James Shorter, Shige H Yoshimura, Sami J Barmada, Diego E Rincon-Limas, Wilfried Rossoll
BACKGROUND: Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-β1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology...
December 8, 2022: Molecular Neurodegeneration
Ethan Roy, Wei Cao
No abstract text is available yet for this article.
November 26, 2022: Molecular Neurodegeneration
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