Publications by authors named "Takaomi C Saido"

205 Publications

Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease.

Sci Rep 2021 Mar 31;11(1):7289. Epub 2021 Mar 31.

Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in App mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from App mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.
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http://dx.doi.org/10.1038/s41598-021-86822-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012710PMC
March 2021

Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice.

Arterioscler Thromb Vasc Biol 2021 Mar 25:ATVBAHA120315546. Epub 2021 Mar 25.

Saha Cardiovascular Research Center, University of Kentucky, Lexington. (L.M., M.O., A.J., D.T., W.J., J.J.M., L.Y., A.B., D.A.H., V.S.).

Objective: Cytoskeletal structural proteins maintain cell structural integrity by bridging extracellular matrix with contractile filaments. During abdominal aortic aneurysm (AAA) development, (1) aortic medial degeneration is associated with loss of smooth muscle cell integrity and (2) fibrogenic mesenchymal cells mediate extracellular matrix remodeling. Calpains cleave cytoskeletal proteins that maintain cell structural integrity. Pharmacological inhibition of calpains exert beneficial effects on Ang II (angiotensin II)-induced AAAs in LDLR (low-density receptor deficient) mice. Here, we evaluated the functional contribution of fibrogenic mesenchymal cells-derived calpain-2 on (1) cytoskeletal structural protein and extracellular matrix alterations and (2) AAA progression. Approach and Results: Calpain-2 protein and cytoskeletal protein (filamin and talin) fragmentation are significantly elevated in human and Ang II-induced AAAs in mice. To examine the relative contribution of calpain-2 in AAA development, calpain-2 floxed mice in an LDLr background were bred to mice with a tamoxifen-inducible form of Cre under control of either the ubiquitous promoter, chicken β-actin, or fibrogenic mesenchymal cell-specific promoter, Col1α2. Ubiquitous or fibrogenic mesenchymal cell-specific depletion of calpain-2 in mice suppressed Ang II-induced AAAs, filamin/talin fragmentation, while promoting extracellular matrix protein, collagen in the aortas. Calpain-2 silencing in aortic smooth muscle cells or fibroblasts reduced Ang II-induced filamin fragmentation. In addition, silencing of filamin in aortic SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed rupture of established Ang II-induced AAAs in mice.

Conclusions: Our studies implicate that calpain-2 deficiency prevents (1) Ang II-induced cytoskeletal structural protein fragmentation and AAA development and (2) stabilize and suppress rupture of established AAAs in mice.
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http://dx.doi.org/10.1161/ATVBAHA.120.315546DOI Listing
March 2021

PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, C-GW2580, and C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey.

J Cereb Blood Flow Metab 2021 Mar 24:271678X211004146. Epub 2021 Mar 24.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, C-GW2580, and compared it to a reported CSF1R tracer, C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic C-GW2580- and C-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of -knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, C-GW2580 captured changes in CSF1R availability more sensitively than C-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of C-CPPC. In summary, our results demonstrated that C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.
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http://dx.doi.org/10.1177/0271678X211004146DOI Listing
March 2021

Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model.

Mol Neurodegener 2021 03 22;16(1):18. Epub 2021 Mar 22.

Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA.

Background: Recent studies suggest that microglia contribute to tau pathology progression in Alzheimer's disease. Amyloid plaque accumulation transforms microglia, the primary innate immune cells in the brain, into neurodegenerative microglia (MGnD), which exhibit enhanced phagocytosis of plaques, apoptotic neurons and dystrophic neurites containing aggregated and phosphorylated tau (p-tau). It remains unclear how microglia promote disease progression while actively phagocytosing pathological proteins, therefore ameliorating pathology.

Methods: Adeno-associated virus expressing P301L tau mutant (AAV-P301L-tau) was stereotaxically injected into the medial entorhinal cortex (MEC) in C57BL/6 (WT) and humanized APP mutant knock-in homozygote (App) mice at 5 months of age. Mice were fed either chow containing a colony stimulating factor-1 receptor inhibitor (PLX5622) or control chow from 4 to 6 months of age to test the effect of microglia depletion. Animals were tested at 6 months of age for immunofluorescence, biochemistry, and FACS of microglia. In order to monitor microglial extracellular vesicle secretion in vivo, a novel lentiviral EV reporter system was engineered to express mEmerald-CD9 (mE-CD9) specifically in microglia, which was injected into the same region of MEC.

Results: Expressing P301L tau mutant in the MEC induced tau propagation to the granule cell layer of the hippocampal dentate gyrus, which was significantly exacerbated in App mice compared to WT control mice. Administration of PLX5622 depleted nearly all microglia in mouse brains and dramatically reduced propagation of p-tau in WT and to a greater extent in App mice, although it increased plaque burden and plaque-associated p-tau dystrophic neurites. Plaque-associated MGnD microglia strongly expressed an EV marker, tumor susceptibility gene 101, indicative of heightened synthesis of EVs. Intracortical injection of mE-CD9 lentivirus successfully induced microglia-specific expression of mE-CD9 EV particles, which were significantly enhanced in Mac2 MGnD microglia compared to Mac2 homeostatic microglia. Finally, consecutive intracortical injection of mE-CD9 lentivirus and AAV-P301L-tau into App mice revealed encapsulation of p-tau in microglia-specific mE-CD9 EVs as determined by super-resolution microscopy and immuno-electron microscopy.

Discussion: Our findings suggest that MGnD microglia hyper-secrete p-tau EVs while compacting Aβ plaques and clearing NP tau, which we propose as a novel mechanistic link between amyloid plaque deposition and exacerbation of tau propagation in App mice.
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http://dx.doi.org/10.1186/s13024-021-00440-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986521PMC
March 2021

Early Identification of Alzheimer's Disease in Mouse Models: Application of Deep Neural Network Algorithm to Cognitive Behavioral Parameters.

iScience 2021 Mar 16;24(3):102198. Epub 2021 Feb 16.

Hitachi, Ltd, Research and Development Group, Center for Exploratory Research, Kokubunji, Tokyo 185-8601, Japan.

Alzheimer's disease (AD) is a worldwide burden. Diagnosis is complicated by the fact that AD is asymptomatic at an early stage. Studies using AD-modeled animals offer important and useful insights. Here, we classified mice with a high risk of AD at a preclinical stage by using only their behaviors. Wild-type and knock-in AD-modeled ( ) mice were raised, and their cognitive behaviors were assessed in an automated monitoring system. The classification utilized a machine learning method, i.e., a deep neural network, together with optimized stepwise feature selection and cross-validation. The AD risk could be identified on the basis of compulsive and learning behaviors (89.3% ± 9.8% accuracy) shown by AD-modeled mice in the early age (i.e., 8-12 months old) when the AD symptomatic cognitions were relatively underdeveloped. This finding reveals the advantage of machine learning in unveiling the importance of compulsive and learning behaviors for early AD diagnosis in mice.
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http://dx.doi.org/10.1016/j.isci.2021.102198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937558PMC
March 2021

Tooth Loss Induces Memory Impairment and Gliosis in App Knock-In Mouse Models of Alzheimer's Disease.

J Alzheimers Dis 2021 Mar 9. Epub 2021 Mar 9.

Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Background: Epidemiological studies have shown that tooth loss is associated with Alzheimer's disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear.

Objective: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in AppNL - G - F mice.

Methods: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL - G - F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-β (Aβ) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aβ ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis.

Results: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation.

Conclusion: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.
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http://dx.doi.org/10.3233/JAD-201055DOI Listing
March 2021

Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor.

Brain Commun 2021 29;3(1):fcab011. Epub 2021 Jan 29.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer's disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (). However, it is yet to be clarified in Alzheimer's disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer's disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer's disease and non-Alzheimer's disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and mice). By contrast, neuritic plaques in Alzheimer's disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer's disease-related neurodegenerative processes.
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http://dx.doi.org/10.1093/braincomms/fcab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901060PMC
January 2021

Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in App, App, and wild type mice.

Sci Rep 2021 Feb 25;11(1):4678. Epub 2021 Feb 25.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA.

Epigenetic mechanisms occurring in the brain as well as alterations in the gut microbiome composition might contribute to Alzheimer's disease (AD). Human amyloid precursor protein knock-in (KI) mice contain the Swedish and Iberian mutations (App) or those two and also the Arctic mutation (App). In this study, we assessed whether behavioral and cognitive performance in 6-month-old App, App, and C57BL/6J wild-type (WT) mice was associated with the gut microbiome, and whether the genotype modulates this association. The genotype effects observed in behavioral tests were test-dependent. The biodiversity and composition of the gut microbiome linked to various aspects of mouse behavioral and cognitive performance but differences in genotype modulated these relationships. These genotype-dependent associations include members of the Lachnospiraceae and Ruminococcaceae families. In a subset of female mice, we assessed DNA methylation in the hippocampus and investigated whether alterations in hippocampal DNA methylation were associated with the gut microbiome. Among other differentially methylated regions, we identified a 1 Kb region that overlapped ing 3'UTR of the Tomm40 gene and the promoter region of the Apoe gene that and was significantly more methylated in the hippocampus of App than WT mice. The integrated gut microbiome hippocampal DNA methylation analysis revealed a positive relationship between amplicon sequence variants (ASVs) within the Lachnospiraceae family and methylation at the Apoe gene. Hence, these microbes may elicit an impact on AD-relevant behavioral and cognitive performance via epigenetic changes in AD-susceptibility genes in neural tissue or that such changes in the epigenome can elicit alterations in intestinal physiology that affect the growth of these taxa in the gut microbiome.
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http://dx.doi.org/10.1038/s41598-021-83851-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907263PMC
February 2021

Retinal Thickness Changes Over Time in a Murine AD Model APP .

Front Aging Neurosci 2020 15;12:625642. Epub 2021 Jan 15.

Ramon Castroviejo Ophthalmological Research Institute, Complutense University of Madrid, Madrid, Spain.

Alzheimer's disease (AD) may present retinal changes before brain pathology, suggesting the retina as an accessible biomarker of AD. The present work is a diachronic study using spectral domain optical coherence tomography (SD-OCT) to determine the total retinal thickness and retinal nerve fiber layer (RNFL) thickness in an APP mouse model of AD at 6, 9, 12, 15, 17, and 20 months old compared to wild type (WT) animals. Total retinal thickness and RNFL thickness were determined. The mean total retinal thickness was analyzed following the Early Treatment Diabetic Retinopathy Study sectors. RNFL was measured in six sectors of axonal ring scans around the optic nerve. In the APP group compared to WT animals, the total retinal thickness changes observed were the following: (i) At 6-months-old, a significant thinning in the outer temporal sector was observed; (ii) at 15-months-old a significant thinning in the inner temporal and in the inner and outer inferior retinal sectors was noticed; (iii) at 17-months-old, a significant thickening in the inferior and nasal sectors was found in both inner and outer rings; and (iv) at 20-months-old, a significant thinning in the inner ring of nasal, temporal, and inferior retina and in the outer ring of superior and temporal retina was seen. In RNFL thickness, there was significant thinning in the global analysis and in nasal and inner-temporal sectors at 6 months old. Thinning was also found in the supero-temporal and nasal sectors and global value at 20 months old. In the APP AD model, the retinal thickness showed thinning, possibly produced by neurodegeneration alternating with thickening caused by deposits and neuroinflammation in some areas of the retina. These changes over time are similar to those observed in the human retina and could be a biomarker for AD. The APP AD model may help us better understand the different retinal changes during the progression of AD.
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http://dx.doi.org/10.3389/fnagi.2020.625642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852550PMC
January 2021

Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations.

J Alzheimers Dis 2021 ;80(1):159-174

Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga, Japan.

Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer's disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor.

Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain.

Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA.

Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment.

Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.
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http://dx.doi.org/10.3233/JAD-201174DOI Listing
January 2021

The App mouse retina is a site for preclinical Alzheimer's disease diagnosis and research.

Acta Neuropathol Commun 2021 01 6;9(1). Epub 2021 Jan 6.

Neural Circuit Development and Regeneration Research Group, Department of Biology, University of Leuven (KU Leuven), Naamsestraat 61, Box 2464, 3000, Leuven, Belgium.

In this study, we report the results of a comprehensive phenotyping of the retina of the App mouse. We demonstrate that soluble Aβ accumulation is present in the retina of these mice early in life and progresses to Aβ plaque formation by midlife. This rising Aβ burden coincides with local microglia reactivity, astrogliosis, and abnormalities in retinal vein morphology. Electrophysiological recordings revealed signs of neuronal dysfunction yet no overt neurodegeneration was observed and visual performance outcomes were unaffected in the App mouse. Furthermore, we show that hyperspectral imaging can be used to quantify retinal Aβ, underscoring its potential as a biomarker for AD diagnosis and monitoring. These findings suggest that the App retina mimics the early, preclinical stages of AD, and, together with retinal imaging techniques, offers unique opportunities for drug discovery and fundamental research into preclinical AD.
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http://dx.doi.org/10.1186/s40478-020-01102-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788955PMC
January 2021

Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease.

Acta Neuropathol Commun 2021 01 5;9(1). Epub 2021 Jan 5.

Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Aichi, 464-8601, Japan.

Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, App with amyloid pathology, rTg4510 with tauopathy, and SOD1 with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1 microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.
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http://dx.doi.org/10.1186/s40478-020-01099-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786928PMC
January 2021

Prodromal Alzheimer's Disease: Constitutive Upregulation of Neuroglobin Prevents the Initiation of Alzheimer's Pathology.

Front Neurosci 2020 3;14:562581. Epub 2020 Dec 3.

Molecular Neuropathology, Physiological and Pathological Processes, Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, Spain.

In humans, a considerable number of the autopsy samples of cognitively normal individuals aged between 57 and 102 years have revealed the presence of amyloid plaques, one of the typical signs of AD, indicating that many of us use mechanisms that defend ourselves from the toxic consequences of Aß. The human APP NL/F (hAPP NL/F) knockin mouse appears as the ideal mouse model to identify these mechanisms, since they have high Aß42 levels at an early age and moderate signs of disease when old. Here we show that in these mice, the brain levels of the hemoprotein Neuroglobin (Ngb) increase with age, in parallel with the increase in Aß42. , in wild type neurons, exogenous Aß increases the expression of Ngb and Ngb over-expression prevents Aß toxicity. , in old hAPP NL/F mice, Ngb knockdown leads to dendritic tree simplification, an early sign of Alzheimer's disease. These results could indicate that Alzheimer's symptoms may start developing at the time when defense mechanisms start wearing out. In agreement, analysis of plasma Ngb levels in aged individuals revealed decreased levels in those whose cognitive abilities worsened during a 5-year longitudinal follow-up period.
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http://dx.doi.org/10.3389/fnins.2020.562581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744294PMC
December 2020

A potential defense mechanism against amyloid deposition in cerebellum.

Biochem Biophys Res Commun 2021 Jan 16;535:25-32. Epub 2020 Dec 16.

Laboratory of Neuropathology, Graduate School of Life and Medical Sciences, Doshisha University, Kyoto, Japan. Electronic address:

Amyloid-β (Aβ) is the major component of senile plaques in Alzheimer's disease (AD) brains. Senile plaques are generally observed in cerebral cortex (CTX) rather than cerebellum (CBL) in AD patients. However, it is not clear why CBL has less Aβ deposition than CTX. It is very important to elucidate the mechanism of suppressing Aβ deposition in CBL, because it contributes to understanding of not only AD pathogenesis but also prevention and cure of AD. In this study, we explored to figure out the potential mechanism of reducing Aβ deposition in CBL. We observed higher age-dependent elevation of Aβ level in CTX rather than CBL of human APP knock-in AD model mice, although we detected no significant differences in the levels of interstitial fluid Aβ in these brain tissues. These data imply that less Aβ deposition in CBL is due to enhanced Aβ clearance rather than altered Aβ production in CBL. To gain insights into Aβ clearance in CBL, we injected fluorescence-labeled Aβ in brain tissues. Importantly diffusion area of fluorescent Aβ in CBL was roughly six-times larger than that in CTX within 2 h of injection. In addition, injected Aβ area in CBL decreased sharply after 24 h and CBL-injected Aβ was robustly detected in deep cervical lymph nodes (DcLNs). In contrast, diffusion area of fluorescent Aβ in CTX was consistent up to 72 h and CTX-injected Aβ was faintly detected in DcLNs. Our data suggest that enhanced Aβ drainage in association with meningeal lymphatic system is responsible for less Aβ deposition in CBL.
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http://dx.doi.org/10.1016/j.bbrc.2020.12.036DOI Listing
January 2021

Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals.

Cell Syst 2021 Feb 15;12(2):141-158.e9. Epub 2020 Dec 15.

Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer's disease (AD). To observe protein turnover at early stages of amyloid beta (Aβ) proteotoxicity, we performed pulse-chase proteomics on mouse brains in three genetic models of AD that knock in alleles of amyloid precursor protein (APP) prior to the accumulation of plaques and during disease progression. At initial stages of Aβ accumulation, the turnover of proteins associated with presynaptic terminals is selectively impaired. Presynaptic proteins with impaired turnover, particularly synaptic vesicle (SV)-associated proteins, have elevated levels, misfold in both a plaque-dependent and -independent manner, and interact with APP and Aβ. Concurrent with elevated levels of SV-associated proteins, we found an enlargement of the SV pool as well as enhancement of presynaptic potentiation. Together, our findings reveal that the presynaptic terminal is particularly vulnerable and represents a critical site for manifestation of initial AD etiology. A record of this paper's transparent peer review process is included in the Supplemental Information.
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http://dx.doi.org/10.1016/j.cels.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897324PMC
February 2021

Touchscreen-based location discrimination and paired associate learning tasks detect cognitive impairment at an early stage in an App knock-in mouse model of Alzheimer's disease.

Mol Brain 2020 11 13;13(1):147. Epub 2020 Nov 13.

Research Center for Next-Generation Drug Development, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline with accumulation of amyloid beta (Aβ) and neurofibrillary tangles that usually begins 15-30 years before clinical diagnosis. Rodent models that recapitulate aggressive Aβ and/or the pathology of neurofibrillary tangles are essential for AD research. Accordingly, non-invasive early detection systems in these animal models are required to evaluate the phenotypic changes, elucidate the mechanism of disease progression, and facilitate development of novel therapeutic approaches. Although many behavioral tests efficiently reveal cognitive impairments at the later stage of the disease in AD models, it has been challenging to detect such impairments at the early stage. To address this issue, we subjected 4-6-month-old male App knock-in (App-KI) mice to touchscreen-based location discrimination (LD), different object-location paired-associate learning (dPAL), and reversal learning tests, and compared the results with those of the classical Morris water maze test. These tests are mainly dependent on the brain regions prone to Aβ accumulation at the earliest stages of the disease. At 4-6 months, considered to represent the early stage of disease when mice exhibit initial deposition of Aβ and slight gliosis, the classical Morris water maze test revealed no difference between groups, whereas touchscreen-based LD and dPAL tasks revealed significant impairments in task performance. Our report is the first to confirm that a systematic touchscreen-based behavioral test battery can sensitively detect the early stage of cognitive decline in an AD-linked App-KI mouse model. This system could be applied in future translational research.
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http://dx.doi.org/10.1186/s13041-020-00690-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664057PMC
November 2020

Impact of Hyperhomocysteinemia and Different Dietary Interventions on Cognitive Performance in a Knock-in Mouse Model for Alzheimer's Disease.

Nutrients 2020 Oct 23;12(11). Epub 2020 Oct 23.

Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.

Background: Hyperhomocysteinemia is considered a possible contributor to the complex pathology of Alzheimer's disease (AD). For years, researchers in this field have discussed the apparent detrimental effects of the endogenous amino acid homocysteine in the brain. In this study, the roles of hyperhomocysteinemia driven by vitamin B deficiency, as well as potentially beneficial dietary interventions, were investigated in the novel knock-in mouse model for AD, simulating an early stage of the disease.

Methods: Urine and serum samples were analyzed using a validated LC-MS/MS method and the impact of different experimental diets on cognitive performance was studied in a comprehensive behavioral test battery. Finally, we analyzed brain samples immunohistochemically in order to assess amyloid-β (Aβ) plaque deposition.

Results: Behavioral testing data indicated subtle cognitive deficits in compared to C57BL/6J wild type mice. Elevation of homocysteine and homocysteic acid, as well as counteracting dietary interventions, mostly did not result in significant effects on learning and memory performance, nor in a modified Aβ plaque deposition in 35-week-old mice.

Conclusion: Despite prominent Aβ plaque deposition, the model merely displays a very mild AD-like phenotype at the investigated age. Older mice should be tested in order to further investigate potential effects of hyperhomocysteinemia and dietary interventions.
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http://dx.doi.org/10.3390/nu12113248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690745PMC
October 2020

Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in.

Neurobiol Dis 2020 11 25;145:105059. Epub 2020 Aug 25.

Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA; Departments of Neurology, Yale University School of Medicine, New Haven, CT, USA; Departments of Neuroscience, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

There is a strong unmet need for translational progress towards Alzheimer's disease (AD) modifying therapy. Unfortunately, preclinical modeling of the disease has been disappointing, relying primarily on transgenic mouse overexpression of rare dominant mutations. Clinical manifestation of AD symptoms is known to reflect interaction between environmental and genetic risks. Mild traumatic brain injury (mTBI) is an environmental risk for dementia, including Alzheimer's, but there has been limited mechanistic analysis of mTBI contribution to AD. Here, we investigate the interplay between mTBI and Aβ precursor protein gene mutation in AD pathogenesis. We employed a knock-in (KI) model of AD that expresses the Aß-containing exons from human APP bearing the Swedish and Iberian mutations, namely App mice. Without environmental risk, this genetic variation yields minimal mouse symptomatology. Anesthetized 4-month-old KI mice and their age-matched wild type (WT) controls were subjected to repeated mild closed head injury (rmCHI), once daily for 14 days. Anesthetized, uninjured genotype- and age-matched mice were used as sham controls. At 3- and 8-months post-injury, amyloid-β, phospho-tau and Iba1 expression in the injured KI cortices were assessed. Our data reveal that rmCHI enhances accumulation of amyloid-β and hyperphosphorylated tau inclusions, as well as neuroinflammation in App mice. Furthermore, novel object recognition and Morris water maze tests demonstrated that rmCHI greatly exacerbates persistent cognitive deficits in APP mice. Therefore, study of gene-environment interaction demonstrates that combining risk factors provides a more robust model for AD, and that repeated mTBI substantially accelerates AD pathology in a genetically susceptible situation.
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http://dx.doi.org/10.1016/j.nbd.2020.105059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572902PMC
November 2020

Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer's Disease.

Cell 2020 08 22;182(4):976-991.e19. Epub 2020 Jul 22.

VIB Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven 3000, Belgium; UK Dementia Research Institute at University College London, London WC1E 6BT, UK. Electronic address:

Although complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer's disease (AD), little is known about the molecular changes and cellular interactions that characterize this response. We investigate here, in an AD mouse model, the transcriptional changes occurring in tissue domains in a 100-μm diameter around amyloid plaques using spatial transcriptomics. We demonstrate early alterations in a gene co-expression network enriched for myelin and oligodendrocyte genes (OLIGs), whereas a multicellular gene co-expression network of plaque-induced genes (PIGs) involving the complement system, oxidative stress, lysosomes, and inflammation is prominent in the later phase of the disease. We confirm the majority of the observed alterations at the cellular level using in situ sequencing on mouse and human brain sections. Genome-wide spatial transcriptomics analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.
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http://dx.doi.org/10.1016/j.cell.2020.06.038DOI Listing
August 2020

Disrupted Place Cell Remapping and Impaired Grid Cells in a Knockin Model of Alzheimer's Disease.

Neuron 2020 09 21;107(6):1095-1112.e6. Epub 2020 Jul 21.

Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Japan Science and Technology Agency, Tokyo, Japan. Electronic address:

Patients with Alzheimer's disease (AD) suffer from spatial memory impairment and wandering behavior, but the brain circuit mechanisms causing such symptoms remain largely unclear. In healthy brains, spatially tuned hippocampal place cells and entorhinal grid cells exhibit distinct spike patterns in different environments, a circuit function called "remapping." We tested remapping in amyloid precursor protein knockin (APP-KI) mice with impaired spatial memory. CA1 neurons, including place cells, showed disrupted remapping, although their spatial tuning was only mildly diminished. Medial entorhinal cortex (MEC) neurons severely lost their spatial tuning and grid cells were almost absent. Fast gamma oscillatory coupling between the MEC and CA1 was also impaired. Mild disruption of MEC grid cells emerged in younger APP-KI mice, although the spatial memory and CA1 remapping of the animals remained intact. These results point to remapping impairment in the hippocampus, possibly linked to grid cell disruption, as circuit mechanisms underlying spatial memory impairment in AD.
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http://dx.doi.org/10.1016/j.neuron.2020.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529950PMC
September 2020

Analysis of Taste Sensitivities in App Knock-In Mouse Model of Alzheimer's Disease.

J Alzheimers Dis 2020 ;76(3):997-1004

Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.

Background: Some studies have reported a decline in taste sensitivities in patients with Alzheimer's disease. However, the detail remains unknown.

Objective: We investigated the effect of cognitive impairment on taste sensitivity using an App knock-in mouse model of Alzheimer's disease.

Methods: Behavioral assays, a brief access test, and a 48 h two-bottle preference test, to assess taste sensitivities were started from 12 months of age in mice that were confirmed to have impaired cognition.

Results: In the assays, there was no significant difference in taste sensitivities between wild type and App knock-in mice. Additionally, no apparent difference was observed in the expression of taste markers in their taste bud cells.

Conclusion: We concluded that cognitive impairment might not greatly affect taste sensitivity.
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http://dx.doi.org/10.3233/JAD-200284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504995PMC
January 2020

Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models.

Elife 2020 06 8;9. Epub 2020 Jun 8.

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid β (Aβ) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aβ Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aβ deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Aβ, rather than dystrophic neurites, suggesting that fibrillar Aβ may trigger the AD-associated microglial phenotype and the observed functional decline. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.
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http://dx.doi.org/10.7554/eLife.54083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279888PMC
June 2020

Amyloid β induces interneuron-specific changes in the hippocampus of APPNL-F mice.

PLoS One 2020 29;15(5):e0233700. Epub 2020 May 29.

Department of Cellular and Network Neurobiology, Institute of Experimental Medicine, HAS, Budapest, Hungary.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and amyloid-beta (Aβ) depositions generated by the proteolysis of amyloid precursor protein (APP) in the brain. In APPNL-F mice, APP gene was humanized and contains two familial AD mutations, and APP-unlike other mouse models of AD-is driven by the endogenous mouse APP promoter. Similar to people without apparent cognitive dysfunction but with heavy Aβ plaque load, we found no significant decline in the working memory of adult APPNL-F mice, but these mice showed decline in the expression of normal anxiety. Using immunohistochemistry and 3D block-face scanning electron microscopy, we found no changes in GABAA receptor positivity and size of somatic and dendritic synapses of hippocampal interneurons. We did not find alterations in the level of expression of perineuronal nets around parvalbumin (PV) interneurons or in the density of PV- or somatostatin-positive hippocampal interneurons. However, in contrast to other investigated cell types, PV interneuron axons were occasionally mildly dystrophic around Aβ plaques, and the synapses of PV-positive axon initial segment (AIS)-targeting interneurons were significantly enlarged. Our results suggest that PV interneurons are highly resistant to amyloidosis in APPNL-F mice and amyloid-induced increase in hippocampal pyramidal cell excitability may be compensated by PV-positive AIS-targeting cells. Mechanisms that make PV neurons more resilient could therefore be exploited in the treatment of AD for mitigating Aβ-related inflammatory effects on neurons.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233700PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259556PMC
August 2020

Versatile whole-organ/body staining and imaging based on electrolyte-gel properties of biological tissues.

Nat Commun 2020 04 27;11(1):1982. Epub 2020 Apr 27.

Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Whole-organ/body three-dimensional (3D) staining and imaging have been enduring challenges in histology. By dissecting the complex physicochemical environment of the staining system, we developed a highly optimized 3D staining imaging pipeline based on CUBIC. Based on our precise characterization of biological tissues as an electrolyte gel, we experimentally evaluated broad 3D staining conditions by using an artificial tissue-mimicking material. The combination of optimized conditions allows a bottom-up design of a superior 3D staining protocol that can uniformly label whole adult mouse brains, an adult marmoset brain hemisphere, an ~1 cm tissue block of a postmortem adult human cerebellum, and an entire infant marmoset body with dozens of antibodies and cell-impermeant nuclear stains. The whole-organ 3D images collected by light-sheet microscopy are used for computational analyses and whole-organ comparison analysis between species. This pipeline, named CUBIC-HistoVIsion, thus offers advanced opportunities for organ- and organism-scale histological analysis of multicellular systems.
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http://dx.doi.org/10.1038/s41467-020-15906-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184626PMC
April 2020

Progressive Changes in Sleep and Its Relations to Amyloid-β Distribution and Learning in Single Knock-In Mice.

eNeuro 2020 Mar/Apr;7(2). Epub 2020 Apr 29.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan

Alzheimer's disease (AD) patients often suffer from sleep disturbances. Alterations in sleep, especially rapid eye movement sleep (REMS), can precede the onset of dementia. To accurately characterize the sleep impairments accompanying AD and their underlying mechanisms using animal models, it is crucial to use models in which brain areas are affected in a manner similar to that observed in the actual patients. Here, we focused on mice, in which expression levels and patterns of mutated amyloid precursor protein (APP) follow the endogenous patterns. We characterized the sleep architecture of male homozygous and heterozygous mice at two ages (six and 12 months). At six months, homozygous mice exhibited reduced REMS, which was further reduced at 12 months together with a slight reduction in non-REMS (NREMS). By contrast, heterozygous mice exhibited an overall normal sleep architecture. Homozygous mice also exhibited decreased electroencephalogram γ to δ power ratio during REMS from six months, resembling the electroencephalogram slowing phenomenon observed in preclinical or early stages of AD. In addition, homozygous mice showed learning and memory impairments in the trace fear conditioning (FC) at both ages, and task performance strongly correlated with REMS amount at 12 months. Finally, histologic analyses revealed that amyloid-β accumulation in the pontine tegmental area and ventral medulla followed a course similar to that of the REMS reduction. These findings support the notion that changes in REMS are an early marker of AD and provide a starting point to address the mechanism of sleep deficits in AD and the effects on cognition.
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http://dx.doi.org/10.1523/ENEURO.0093-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196722PMC
April 2020

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer's Disease-Related Pathological Progression in the Hippocampus of Mice.

Front Pharmacol 2020 11;11:307. Epub 2020 Mar 11.

System Emotional Science, Faculty of Medicine, University of Toyama, Toyama, Japan.

Growing evidence suggests that oxidative stress due to amyloid β (Aβ) accumulation is involved in Alzheimer's disease (AD) through the formation of amyloid plaque, which leads to hyperphosphorylation of tau, microglial activation, and cognitive deficits. The dysfunction or phenotypic loss of parvalbumin (PV)-positive neurons has been implicated in cognitive deficits. Astaxanthin is one of carotenoids and known as a highly potent antioxidant. We hypothesized that astaxanthin's antioxidant effects may prevent the onset of cognitive deficits in AD by preventing AD pathological processes associated with oxidative stress. In the present study, we investigated the effects of astaxanthin intake on the cognitive and pathological progression of AD in a mouse model of AD. The mice were fed with or without astaxanthin from 5-to-6 weeks old, and cognitive functions were evaluated using a Barnes maze test at 6 months old. PV-positive neurons were investigated in the hippocampus. Aβ42 deposits, accumulation of microglia, and phosphorylated tau (pTau) were immunohistochemically analyzed in the hippocampus. The hippocampal anti-oxidant status was also investigated. The Barnes maze test indicated that astaxanthin significantly ameliorated memory deficits. Astaxanthin reduced Aβ42 deposition and pTau-positive areal fraction, while it increased PV-positive neuron density and microglial accumulation per unit fraction of Aβ42 deposition in the hippocampus. Furthermore, astaxanthin increased total glutathione (GSH) levels, although 4-hydroxy-2,3-trans-nonenal (4-HNE) protein adduct levels (oxidative stress marker) remained high in the astaxanthin supplemented mice. The results indicated that astaxanthin ameliorated memory deficits and significantly reversed AD pathological processes (Aβ42 deposition, pTau formation, GSH decrease, and PV-positive neuronal deficits). The elevated GSH levels and resultant recovery of PV-positive neuron density, as well as microglial activation, may prevent these pathological processes.
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http://dx.doi.org/10.3389/fphar.2020.00307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078363PMC
March 2020

Oral glutathione administration inhibits the oxidative stress and the inflammatory responses in App knock-in mice.

Neuropharmacology 2020 05 1;168:108026. Epub 2020 Mar 1.

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Electronic address:

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by the presence of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. Reduced antioxidants and increased oxidative stress and inflammation are responsible for the pathological features characteristic of an AD brain. We observed decreased levels of the reduced form of glutathione (GSH), the most abundant brain antioxidant, and decreased GSH/glutathione disulfide (GSSG) ratios in App knock-in (NL-G-F) mouse brains. Repeated oral GSH administration for 3 weeks dose-dependently increased GSH levels and restored the GSH/GSSH ratio. Consistent with the restoration of GSH levels, the levels of 4-hydroxy-2-nonenal (4-HNE), a marker of oxidative stress, were significantly decreased in the hippocampus of NL-G-F mice. Additionally, inflammatory responses, such as microgliosis and increased mRNA expression of inflammatory cytokines, were also inhibited. Moreover, behavioral deficits including cognitive decline, depressive-like behaviors, and anxiety-related behaviors observed in NL-G-F mice were significantly improved by oral and chronic GSH administration. Taken together, our data suggest that oral GSH administration is an attractive therapeutic strategy to reduce the excessive oxidative stress and inflammatory responses in the AD brain.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108026DOI Listing
May 2020

Nrf2 Suppresses Oxidative Stress and Inflammation in Knock-In Alzheimer's Disease Model Mice.

Mol Cell Biol 2020 02 27;40(6). Epub 2020 Feb 27.

Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan

Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether Nrf2 prevents Alzheimer's disease (AD), AD model knock-in ( ) mice were studied in combination with genetic Nrf2 induction model mice. While mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in :: mice. Matrix-assisted laser desorption ionization-mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in :: mouse brains compared to mouse brains. Genetic Nrf2 induction in mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PlsPE) level as an AD biomarker. PlsPE containing polyunsaturated fatty acids was decreased in the mouse brain, but Nrf2 induction attenuated this decline. To evaluate whether pharmacological induction of Nrf2 elicits beneficial effects for AD treatment, we tested the natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of mice in the passive-avoidance task. These results demonstrate that the induction of Nrf2 ameliorates cognitive impairment in the AD model mouse by suppressing oxidative stress and neuroinflammation, suggesting that Nrf2 is an important therapeutic target of AD.
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http://dx.doi.org/10.1128/MCB.00467-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048263PMC
February 2020

Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model.

Mol Neurodegener 2020 01 8;15(1). Epub 2020 Jan 8.

VIB Center for Brain & Disease Research, Leuven, Belgium.

The amyloid-β (Aβ) peptide, the primary constituent of amyloid plaques found in Alzheimer's disease (AD) brains, is derived from sequential proteolytic processing of the Amyloid Precursor Protein (APP). However, the contribution of different cell types to Aβ deposition has not yet been examined in an in vivo, non-overexpression system. Here, we show that endogenous APP is highly expressed in a heterogeneous subset of GABAergic interneurons throughout various laminae of the hippocampus, suggesting that these cells may have a profound contribution to AD plaque pathology. We then characterized the laminar distribution of amyloid burden in the hippocampus of an APP knock-in mouse model of AD. To examine the contribution of GABAergic interneurons to plaque pathology, we blocked Aβ production specifically in these cells using a cell type-specific knock-out of BACE1. We found that during early stages of plaque deposition, interneurons contribute to approximately 30% of the total plaque load in the hippocampus. The greatest contribution to plaque load (75%) occurs in the stratum pyramidale of CA1, where plaques in human AD cases are most prevalent and where pyramidal cell bodies and synaptic boutons from perisomatic-targeting interneurons are located. These findings reveal a crucial role of GABAergic interneurons in the pathology of AD. Our study also highlights the necessity of using APP knock-in models to correctly evaluate the cellular contribution to amyloid burden since APP overexpressing transgenic models drive expression in cell types according to the promoter and integration site and not according to physiologically relevant expression mechanisms.
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http://dx.doi.org/10.1186/s13024-019-0356-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950898PMC
January 2020

Increased levels of Aβ42 decrease the lifespan of ob/ob mice with dysregulation of microglia and astrocytes.

FASEB J 2020 02 16;34(2):2425-2435. Epub 2019 Dec 16.

Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Morioka, Japan.

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/diabetes and AD significantly reduce life expectancy. We generated App knock-in; ob/ob mice by crossing App knock-in mice and ob/ob mice to investigate whether amyloid-β (Aβ) affects the lifespan of ob/ob mice. App knock-in; ob/ob mice displayed the shortest lifespan compared to wild-type mice, App knock-in mice, and ob/ob mice. Notably, the Aβ42 levels were increased at minimum levels before deposition in App knock-in mice and App knock-in; ob/ob mice at 18 months of age. No differences in the levels of several neuronal markers were observed between mice at this age. However, we observed increased levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in App knock-in; ob/ob mice, while the levels of several microglial markers, including CD11b, TREM2, and DAP12, were decreased in both ob/ob mice and App knock-in; ob/ob mice. The increase in GFAP levels was not observed in young App knock-in; ob/ob mice. Thus, the increased Aβ42 levels may decrease the lifespan of ob/ob mice, which is associated with the dysregulation of microglia and astrocytes in an age-dependent manner. Based on these findings, the imbalance in these neuroinflammatory cells may provide a clue to the mechanisms by which the interaction between obesity/diabetes and early AD reduces life expectancy.
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http://dx.doi.org/10.1096/fj.201901028RRDOI Listing
February 2020