Protection of TGF-β1 against Neuroinflammation and Neurodegeneration in Aβ1–42-Induced Alzheimer’s Disease Model Rats

• Published in: PloS one Vol. 10; no. 2; p. e0116549
• Main Authors: Chen, Jia-Hui, Ke, Kai-Fu, Lu, Jian-Hua, Qiu, Yi-Hua, Peng, Yu-Ping
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.02.2015; Public Library of Science (PLoS)
• Subjects: Administration, Intranasal; Alzheimer Disease - chemically induced; Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - toxicity; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - therapeutic use; Apoptosis; Blood-brain barrier; Brain; Brain-derived neurotrophic factor; CD4 antigen; Cerebrospinal fluid; Cytokines; Cytokines - metabolism; Disease; Disease Models, Animal; Glial cell line-derived neurotrophic factor; Hippocampus; Hypothalamus; Hypothalamus - metabolism; Immunosuppression; Inflammation; Inflammation - prevention & control; Injection; Injections; Insulin-like growth factor I; Interleukin 10; Interleukin 17; Interleukin 2; Interleukin 22; Laboratory animals; Lymphocytes; Lymphocytes T; Medicine; Nerve Degeneration - pathology; Nerve Degeneration - prevention & control; Neurodegeneration; Neurogenesis; Neuroglia - metabolism; Neuroglia - pathology; Neuronal-glial interactions; Neuroprotection; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - therapeutic use; Neurotoxicity; Neurotrophic factors; Nitric-oxide synthase; Pathogenesis; Pathology; Peptide Fragments - toxicity; Physiology; Rats; Rats, Sprague-Dawley; Rodents; Transforming Growth Factor beta1 - administration & dosage; Transforming Growth Factor beta1 - therapeutic use; Transforming growth factor-a; Transforming growth factor-b1; γ-Interferon; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116549

Neuroinflammation has been reported to be associated with Alzheimer's disease (AD) pathogenesis. Neuroinflammation is generally considered as an outcome of glial activation; however, we recently demonstrated that T helper (Th)17 cells, a subpopulation of proinflammatory CD4+ T cells, are also involved in AD pathogenesis. Transforming growth factor (TGF)-β1, a cytokine that can be expressed in the brain, can be immunosuppressive, but its effects on lymphocyte-mediated neuroinflammation in AD pathogenesis have not been well addressed. In the current study we administered TGF-β1 via intracerebroventricle (ICV) and intranasal (IN) routes in AD model rats to investigate its antiinflammatory and neuroprotective effects. The AD rat model was prepared by bilateral hippocampal injection of amyloid-β (Aβ)1-42. TGF-β1 was administered via ICV one hour prior to Aβ1-42 injection or via both nares seven days after Aβ1-42 injection. ICV administration of TGF-β1 before Aβ1-42 injection remarkably ameliorated Aβ1-42-induced neurodegeneration and prevented Aβ1-42-induced increases in glia-derived proinflammatory mediators (TNF-α, IL-1β and iNOS), as well as T cell-derived proinflammatory cytokines (IFN-γ, IL-2, IL-17 and IL-22), in the hypothalamus, serum or cerebrospinal fluid (CSF) in a concentration-dependent manner. TGF-β1 pretreatment also prevented Aβ1-42-induced decreases in the neurotrophic factors, IGF-1, GDNF and BDNF, and in the antiinflammatory cytokine, IL-10. Similarly, IN administration of TGF-β1 after Aβ1-42 injection reduced neurodegeneration, elevation of proinflammatory mediators and cytokines, and reduction of neurotrophic and antiinflammatory factors, in the hypothalamus, serum or CSF. These findings suggest that TGF-β1 suppresses glial and T cell-mediated neuroinflammation and thereby alleviates AD-related neurodegeneration. The effectiveness of IN administered TGF-β1 in reducing Aβ1-42 neurotoxicity suggests a possible therapeutic approach in patients with AD.