The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy

Incomplete remyelination is frequent in multiple sclerosis (MS)-lesions, but there is no established marker for recent remyelination. We investigated the role of the oligodendrocyte/myelin protein ermin in de- and remyelination in the cuprizone (CPZ) mouse model, and in MS. The density of ermin+ oligodendrocytes in the brain was significantly decreased after one week of CPZ exposure (p < 0.02). The relative proportion of ermin+ cells compared to cells positive for the late-stage oligodendrocyte marker Nogo-A increased at the onset of remyelination in the corpus callosum (p < 0.02). The density of ermin-positive cells increased in the corpus callosum during the CPZ-phase of extensive remyelination (p < 0.0001). In MS, the density of ermin+ cells was higher in remyelinated lesion areas compared to non-remyelinated areas both in white- (p < 0.0001) and grey matter (p < 0.0001) and compared to normal-appearing white matter (p < 0.001). Ermin immunopositive cells in MS-lesions were not immunopositive for the early-stage oligodendrocyte markers O4 and O1, but a subpopulation was immunopositive for Nogo-A. The data suggest a relatively higher proportion of ermin immunopositivity in oligodendrocytes compared to Nogo-A indicates recent or ongoing remyelination.

Download Full-text

Superior cancer preventive efficacy of low versus high dose of mTOR inhibitor in a mouse model of prostate cancer

Oncotarget ◽

10.18632/oncotarget.27550 ◽

2020 ◽

Vol 11 (15) ◽

pp. 1373-1387

Author(s):

Marina P. Antoch ◽

Michelle Wrobel ◽

Bryan Gillard ◽

Karen K. Kuropatwinski ◽

Ilia Toshkov ◽

...

Keyword(s):

Prostate Cancer ◽

Mouse Model ◽

Mtor Inhibitor ◽

High Dose ◽

Preventive Efficacy

Download Full-text

FTIR imaging of the molecular burden around Aβ deposits in an early-stage 3-Tg-APP-PSP1-TAU mouse model of Alzheimer's disease

The Analyst ◽

10.1039/c6an01797e ◽

2017 ◽

Vol 142 (1) ◽

pp. 156-168 ◽

Cited By ~ 11

Author(s):

Artur Dawid Surowka ◽

Michael Pilling ◽

Alex Henderson ◽

Herve Boutin ◽

Lidan Christie ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Spatial Resolution ◽

Mouse Brain ◽

High Spatial Resolution ◽

Early Stage ◽

Ftir Imaging ◽

Model Of Alzheimer’S Disease ◽

Tau Mouse Model

High spatial resolution FTIR imaging of early-stage 3-Tg-APP-PSP1-TAU mouse brain identifies molecular burden around Aβ deposits.

Download Full-text

A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01505-17 ◽

2018 ◽

Vol 62 (4) ◽

pp. e01505-17 ◽

Cited By ~ 17

Author(s):

R. S. Jumani ◽

K. Bessoff ◽

M. S. Love ◽

P. Miller ◽

E. E. Stebbins ◽

...

Keyword(s):

Mouse Model ◽

Drug Development ◽

Early Stage ◽

New Drugs ◽

Cryptosporidium Hominis ◽

Content Type ◽

Knockout Mouse Model ◽

Malaria Box

ABSTRACTCryptosporidiosis causes life-threatening diarrhea in children under the age of 5 years and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to the need for new drugs, better knowledge of drug properties that drivein vivoefficacy is needed to facilitate drug development. We report the identification of a piperazine-based lead compound forCryptosporidiumdrug development, MMV665917, and a new pharmacodynamic method used for its characterization. The identification of MMV665917 from the Medicines for Malaria Venture Malaria Box was followed by dose-response studies,in vitrotoxicity studies, and structure-activity relationship studies using commercial analogues. The potency of this compound againstCryptosporidium parvumIowa and field isolates was comparable to that againstCryptosporidium hominis. Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a NOD SCID gamma mouse model of chronic cryptosporidiosis. MMV665917 was also efficacious in a gamma interferon knockout mouse model of acute cryptosporidiosis. To determine if efficacy in this mouse model of chronic infection might relate to whether compounds are parasiticidal or parasitistatic forC. parvum, we developed a novelin vitroparasite persistence assay. This assay suggested that MMV665917 was parasiticidal, unlike nitazoxanide, clofazimine, and paromomycin. The assay also enabled determination of the concentration of the compound required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stageCryptosporidiumdrug leads and may aid in planningin vivoefficacy experiments. Collectively, these results identify MMV665917 as a promising lead and establish a new method for characterizing potential anticryptosporidial agents.

Download Full-text

Etoricoxib decreases subchondral bone mass and attenuates biomechanical properties at the early stage of osteoarthritis in a mouse model

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.110144 ◽

2020 ◽

Vol 127 ◽

pp. 110144 ◽

Cited By ~ 3

Author(s):

Bo Liu ◽

Chenchen Ji ◽

Yijie Shao ◽

Ting Liang ◽

Jiaheng He ◽

...

Keyword(s):

Mouse Model ◽

Bone Mass ◽

Subchondral Bone ◽

Early Stage ◽

Biomechanical Properties

Download Full-text

Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS

Nature Communications ◽

10.1038/s41467-020-18949-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Ching Serena Kao ◽

Rebekah van Bruggen ◽

Jihye Rachel Kim ◽

Xiao Xiao Lily Chen ◽

Cadia Chan ◽

...

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Motor Neurons ◽

Neuronal Degeneration ◽

Early Stage ◽

Motor Impairment ◽

Preclinical Research ◽

Cell Degeneration ◽

Promising Tool ◽

Lateral Sclerosis

Abstract A missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research.

Download Full-text