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Ai Ishikawa, Masaki Tokunaga, Jun Maeda, Takeharu Minamihisamatsu, Masafumi Shimojo, Hiroyuki Takuwa, Maiko Ono, Ruiqing Ni, Shigeki Hirano, Satoshi Kuwabara, Bin Ji, Ming-Rong Zhang, Ichio Aoki, Tetsuya Suhara, Makoto Higuchi, Naruhiko Sahara
BACKGROUND: Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood. OBJECTIVE: We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model. METHODS: rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2...
2018: Journal of Alzheimer's Disease: JAD
Andrew Arner, Edward Rockenstein, Michael Mante, Jazmin Florio, Deborah Masliah, Bahar Salehi, Anthony Adame, Cassia Overk, Eliezer Masliah, Robert A Rissman
 Alzheimer's disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD neuropathology...
2018: Journal of Alzheimer's Disease: JAD
Joshua Jackson, Gabby Bianco, Angelo O Rosa, Katrina Cowan, Peter Bond, Oleg Anichtchik, Robert Fern
Early white matter (WM) changes are common in dementia and may contribute to functional decline. We here examine this phenomenon in an induced dementia model for the first time. We report a novel and selective form of myelin injury as the first manifestation of tauopathy in the adult central nervous system. Myelin pathology rapidly followed the induction of a P301 tau mutation associated with fronto-temporal dementia in humans (rTG4510 line). Damage involved focal disruption of the ad-axonal myelin lamella and internal oligodendrocyte tongue process, followed by myelin remodeling with features of re-myelination that included myelin thinning and internodal shortening...
January 8, 2018: Glia
Rana A Eser, Alexander J Ehrenberg, Cathrine Petersen, Sara Dunlop, Maria B Mejia, Claudia K Suemoto, Christine M Walsh, Hima Rajana, Jun Oh, Panos Theofilas, William W Seeley, Bruce L Miller, Thomas C Neylan, Helmut Heinsen, Lea T Grinberg
The brainstem nuclei of the reticular formation (RF) are critical for regulating homeostasis, behavior, and cognition. RF degenerates in tauopathies including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Although the burden of phopho-tau inclusion is high across these diseases, suggesting a similar vulnerability pattern, a distinct RF-associated clinical phenotype in these diseases indicates the opposite. To compare patterns of RF selective vulnerability to tauopathies, we analyzed 5 RF nuclei in tissue from 14 AD, 14 CBD, 10 PSP, and 3 control cases...
January 2, 2018: Journal of Neuropathology and Experimental Neurology
Fong Ping Chong, Khuen Yen Ng, Rhun Yian Koh, Soi Moi Chye
Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive function deficits. There are two major pathological hallmarks that contribute to the pathogenesis of AD which are the presence of extracellular amyloid plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Despite extensive research that has been done on Aβ in the last two decades, therapies targeting Aβ were not very fruitful at treating AD as the efficacy of Aβ therapies observed in animal models is not reflected in human clinical trials...
January 3, 2018: Cellular and Molecular Neurobiology
Shoko Hashimoto, Ayano Ishii, Naoko Kamano, Naoto Watamura, Takashi Saito, Toshio Oshima, Makoto Yokosuka, Takaomi C Saido
Endoplasmic reticulum (ER) stress is believed to play an important role in the etiology of Alzheimer disease (AD). The accumulation of misfolded proteins and perturbation of intracellular calcium homeostasis are thought to underlie the induction of ER stress, resulting in neuronal dysfunction and cell death. Several reports have shown an increased ER stress response in amyloid precursor protein (APP) and presenilin1 (PS1) double transgenic (Tg) AD mouse models. However, it remains unclear whether the ER stress observed in these mouse models is actually caused by AD pathology...
January 3, 2018: Journal of Biological Chemistry
Alexander J Moszczynski, Wendy Strong, Kathy Xu, Ann McKee, Arthur Brown, Michael J Strong
OBJECTIVE: To investigate whether chronic traumatic encephalopathy (CTE) and CTE with amyotrophic lateral sclerosis (CTE-ALS) exhibit features previously observed in other tauopathies of pathologic phosphorylation of microtubule-associated protein tau at Thr175 (pThr175 tau) and Thr231 (pThr231 tau), and glycogen synthase kinase-3β (GSK3β) activation, and whether these pathologic features are a consequence of traumatic brain injury (TBI). METHODS: Tau isoform expression was assayed by western blot in 6 stage III CTE cases...
January 3, 2018: Neurology
X Y Tai, B Bernhardt, M Thom, P Thompson, S Baxendale, M Koepp, N Bernasconi
Cognitive decline is increasingly described as a co-morbidity of temporal lobe epilepsy (TLE). Mechanisms underlying cognitive impairment are not fully understood despite examining clinical factors, such as seizure frequency, and cellular mechanisms of excitotoxicity. We review the neuropsychometry evidence for progressive cognitive decline and examine the pathology and neuroimaging evidence supporting a neurodegenerative process in hippocampal sclerosis (HS)-related TLE. Accelerated cognitive decline is described in groups of adult HS-related TLE patients...
December 30, 2017: Neuropathology and Applied Neurobiology
Koichi Okamoto, Isao Naito, Toshio Fukuda, Keiji Suzuki, Masamitsu Takatama
We report the case of a 72-year-old Japanese woman with moyamoya disease (MMD). She experienced her first intracerebral hemorrhage (ICH) at the age of 32 years, and had nine ICHs and/or intraventricular hemorrhages during the following 40 years. Cerebral angiograms and vascular pathologies at autopsy confirmed that the patient suffered from MMD. Macroscopically, there were brown-colored changes in the subarachnoid space, mainly at the base of the brain and around the cerebellar hemispheres. Microscopically, hemosiderin deposits were observed mainly in the old hemorrhagic lesions and on the surface of the brainstem and cerebellum...
December 27, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Hye-Jin Park, Kang-Woo Lee, Stephanie Oh, Run Yan, Jie Zhang, Thomas G Beach, Charles H Adler, Michael Voronkov, Steven P Braithwaite, Jeffry B Stock, M Maral Mouradian
Hyperphosphorylated tau aggregates are characteristic of tauopathies including progressive supranuclear palsy (PSP) and Alzheimer disease (AD), but factors contributing to pathologic tau phosphorylation are not well understood. Here, we studied the regulation of the major tau phosphatase, the heterotrimeric AB55αC protein phosphatase 2 A (PP2A), in PSP and AD. The assembly and activity of this PP2A isoform are regulated by reversible carboxyl methylation of its catalytic C subunit, while the B subunit confers substrate specificity...
December 21, 2017: Journal of Neuropathology and Experimental Neurology
Chen-Chen Tan, Xiao-Yan Zhang, Lan Tan, Jin-Tai Yu
Tauopathies are morphologically, biochemically, and clinically heterogeneous neurodegenerative diseases defined by the accumulation of abnormal tau proteins in the brain. There is no effective method to prevent and reverse the tauopathies, but this gloomy picture has been changed by recent research advances. Evidences from genetic studies, experimental animal models, and molecular and cell biology have shed light on the main mechanisms of the diseases. The development of radiology and biochemistry, especially the development of PET imaging, will provide important biomarkers for the clinical diagnosis and treatment...
2018: Journal of Alzheimer's Disease: JAD
Brandon Lucke-Wold, Kay Seidel, Rub Udo, Bennet Omalu, Mark Ornstein, Richard Nolan, Charles Rosen, Joel Ross
Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation...
2017: Journal of Neurology and Neurosurgery
Andrea Forgacsova, Jaroslav Galba, Ralph M Garruto, Petra Majerova, Stanislav Katina, Andrej Kovac
Neurotransmitters, small molecules widely distributed in the central nervous system are essential in transmitting electrical signals across neurons via chemical communication. Dysregulation of these chemical signaling molecules is linked to numerous neurological diseases including tauopathies. In this study, a precise and reliable liquid chromatography method was established with tandem mass spectrometry detection for the simultaneous determination of aspartic acid, asparagine, glutamic acid, glutamine, γ-aminobutyric acid, N-acetyl-l-aspartic acid, pyroglutamic acid, acetylcholine and choline in human brain tissue...
December 9, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Akiko Satoh, Koichi M Iijima
The locus coeruleus (LC) is the noradrenaline (norepinephrine, NE)-containing nucleus in the brainstem and innervates into widespread brain regions. This LC-NE system plays a critical role in a variety of brain functions, including attention, arousal, emotion, cognition, and the sleep-wake cycle. The LC is one of the brain regions vulnerable to the occurrence of neurofibrillary tangles (NFTs), which is associated with "primary age-related tauopathy (PART)" that describes the pathology commonly observed in the brains of aged individuals...
December 21, 2017: Brain Research
Kevin H Strang, Cara L Croft, Zachary A Sorrentino, Paramita Chakrabarty, Todd E Golde, Benoit I Giasson
The accumulation of aberrantly aggregated microtubule-associated protein tau (MAPT)1 defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the MAPT gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological tau inclusions in the form of neurofibrillary tangles and Pick bodies, and in some cases glial tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases...
December 19, 2017: Journal of Biological Chemistry
Amrit Mudher, Morvane Colin, Simon Dujardin, Miguel Medina, Ilse Dewachter, Seyedeh Maryam Alavi Naini, Eva-Maria Mandelkow, Eckhard Mandelkow, Luc Buée, Michel Goedert, Jean-Pierre Brion
Emerging experimental evidence suggests that the spread of tau pathology in the brain in Tauopathies reflects the propagation of abnormal tau species along neuroanatomically connected brain areas. This propagation could occur through a "prion-like" mechanism involving transfer of abnormal tau seeds from a "donor cell" to a "recipient cell" and recruitment of normal tau in the latter to generate new tau seeds. This review critically appraises the evidence that the spread of tau pathology occurs via such a "prion-like" mechanism and proposes a number of recommendations for directing future research...
December 19, 2017: Acta Neuropathologica Communications
Alana N Vagnozzi, Phillip F Giannopoulos, Domenico Praticò
Neurodegenerative tauopathies are characterized by pathological accumulation of highly phosphorylated isoforms of tau protein, which leads to progressive neuronal loss. Neuroinflammation often accompanies tau-driven diseases; however, the direct role of neuroinflammation in tauopathies remains unknown. The 5-lipoxygenase (5LO) is a pro-inflammatory enzyme, which produces several bioactive metabolites and is widely expressed in the central nervous system. Previously, our group showed that 5LO influences the Alzheimer's disease (AD) phenotype of APP transgenic mice as well as a mouse model with plaques and tangles...
December 18, 2017: Translational Psychiatry
Jason Schapansky, Saurabh Khasnavis, Mark P DeAndrade, Jonathan D Nardozzi, Samuel R Falkson, Justin D Boyd, John B Sanderson, Tim Bartels, Heather L Melrose, Matthew J LaVoie
Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function...
December 12, 2017: Neurobiology of Disease
Kaoru Yamada
The pathological aggregation of tau protein is a hallmark of a set of neurodegenerative diseases collectively referred to as tauopathies. Tau aggregates independently in each neuron, but this aggregation can also occur in a non-cell autonomous manner in which aggregated tau is transmitted from one cell to another. Such trans-cellular propagation is initiated by the uptake of extracellular tau, which then seeds soluble tau in the recipient cells to spread the tau pathology. Accumulating evidence has demonstrated that tau is not only present in the cytoplasm of neurons but also actively released into the extracellular space...
2017: Frontiers in Neuroscience
Darran Yates
No abstract text is available yet for this article.
December 14, 2017: Nature Reviews. Neuroscience
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