Limits...
Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model.

Gabbita SP, Johnson MF, Kobritz N, Eslami P, Poteshkina A, Varadarajan S, Turman J, Zemlan F, Harris-White ME - PLoS ONE (2015)

Bottom Line: IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation.Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population.IDT is a safe and effective TNFα and innate immune system modulator.

View Article: PubMed Central - PubMed

Affiliation: P2D Bioscience, Inc., Cincinnati, Ohio, United States of America.

ABSTRACT
Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer's Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus

BACE1 Protein.(A) Representative western blot of hippocampal homogenates for BACE1. (B) Densitometry results for BACE1 and Actin were obtained and the changes in BACE1/Actin expressed as % Control. No significant effect of IDT was observed.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4593589&req=5

pone.0137305.g010: BACE1 Protein.(A) Representative western blot of hippocampal homogenates for BACE1. (B) Densitometry results for BACE1 and Actin were obtained and the changes in BACE1/Actin expressed as % Control. No significant effect of IDT was observed.

Mentions: β-Secretase-1 (BACE1), the β-site amyloid precursor protein (APP) cleaving enzyme, is an aspartic protease that promotes Aβ generation [30] and TNFα signaling pathways have been implicated in the regulation of BACE1 activity [31–34]. BACE1 proteins levels were determined by western blot. No significant reduction in BACE1 protein levels with any IDT dose were found (Fig 10).


Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model.

Gabbita SP, Johnson MF, Kobritz N, Eslami P, Poteshkina A, Varadarajan S, Turman J, Zemlan F, Harris-White ME - PLoS ONE (2015)

BACE1 Protein.(A) Representative western blot of hippocampal homogenates for BACE1. (B) Densitometry results for BACE1 and Actin were obtained and the changes in BACE1/Actin expressed as % Control. No significant effect of IDT was observed.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4593589&req=5

pone.0137305.g010: BACE1 Protein.(A) Representative western blot of hippocampal homogenates for BACE1. (B) Densitometry results for BACE1 and Actin were obtained and the changes in BACE1/Actin expressed as % Control. No significant effect of IDT was observed.
Mentions: β-Secretase-1 (BACE1), the β-site amyloid precursor protein (APP) cleaving enzyme, is an aspartic protease that promotes Aβ generation [30] and TNFα signaling pathways have been implicated in the regulation of BACE1 activity [31–34]. BACE1 proteins levels were determined by western blot. No significant reduction in BACE1 protein levels with any IDT dose were found (Fig 10).

Bottom Line: IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation.Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population.IDT is a safe and effective TNFα and innate immune system modulator.

View Article: PubMed Central - PubMed

Affiliation: P2D Bioscience, Inc., Cincinnati, Ohio, United States of America.

ABSTRACT
Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer's Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus