transforming-growth-factor-beta and Cognitive-Dysfunction

Despite its identification as a key checkpoint regulator of microglial activation in Alzheimer's disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood.. Accumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD;Cx3cr1. Disease progression in 5xFAD;Cx3cr1. Cx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1

Topics: Alzheimer Disease; Amyloidogenic Proteins; Amyloidosis; Animals; Cognitive Dysfunction; CX3C Chemokine Receptor 1; Mice; Neurons; Plaque, Amyloid; Transforming Growth Factor beta

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a life-threatening, inherited, nonhypertensive arteriole disease of the brain. Therapeutic strategy for CARASIL is limited because its pathogenesis is not clear. We previously reported the first family with CARASIL in China, which involves a high-temperature requirement serine protease gene mutation (HtrA1. Food maze and water maze experiments were used in the behavioral studies. Pathological studies were carried out by arteriole labeling staining and electron microscopy. The mRNA and protein expression levels of the key factors of TGF-β/Smad signaling pathway (TGF-β, Smad2, Smad3, and Smad4) in the brain of the model mice were detected by immunohistochemistry, real-time quantitative polymerase chain reaction (RT-PCR), and Western blot assay.. The food maze and water maze experiment data showed significant differences between the Mut and wild-type (WT) mice in the first time to find food, the time to contact the escape table for the first time, and the number of times to travel in the escape table quadrant (p < 0.001). The results of vascular labeling staining showed that some small arteries in the brain of Mut mice lost normal structure. The results of electron microscopy showed that the cell morphologies in the cortex and hippocampus of Mut mice were abnormal; the number of synapses was reduced; the walls of capillaries, venules, and arterioles thickened; lumen stenosis and other abnormal phenomenon occurred; and lipofuscin deposition and autophagosomes were found in the hippocampus. Immunohistochemistry, RT-PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF-β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees.. The most significant innovation of this study is the first study on the pathogenesis of CARASIL disease using model animals. The Mut mice can well simulate the pathogenesis of CARASIL in behavioral and pathological aspects. The TGF-β/Smad signaling pathway, which is involved in the pathogenesis of CARASIL, is abnormally upregulated in the brain of Mut mice.

Topics: Alopecia; Animals; Cerebral Arterial Diseases; Cerebral Infarction; Cerebrovascular Disorders; Cognitive Dysfunction; High-Temperature Requirement A Serine Peptidase 1; Leukoencephalopathies; Mice; RNA, Messenger; Signal Transduction; Spinal Diseases; Transforming Growth Factor beta

Postoperative cognitive dysfunction (POCD) is one of the common postoperative complications, which is more common in aged patients. POCD mainly manifests as cognitive function changes after surgery, such as memory decline and inattention. In some severe cases, patients may suffer from personality changes and (or) social behavior decline. The aim of the current study is to confirm the effect and elucidate the mechanism of bone marrow mesenchymal stem cells (BMSCs) in postoperative central inflammatory mice.. Mice were randomly assigned to four groups: sham, sham+BMSCs, model, and BMSCs group. In the model group, mice were intraperitoneally injected 8 mg/kg per day lipopolysaccharide for 5 days. In sham+BMSCs and BMSCs group, BMSCs (1 × 10. In the model group, transforming growth factor β (TGF-β) protein expression was significantly increased, compared with that in the sham group. BMSCs were treated into postoperative central inflammatory mice, which resulted in a decreased of TGF-β protein expression. TGF-β and smad2 protein expression were suppressed, and apoptosis rate and inflammation were inhibited in coculture with BMSCs. The suppression of TGF-β inhibited the effects of BMSCs on apoptosis rate and inflammation in postoperative central inflammatory through a smad2 signaling pathway. The promotion of TGF-β reduced the effects of BMSCs on apoptosis rate and inflammation in postoperative central inflammatory through a smad2 signaling pathway.. The present study demonstrates that BMSCs regulates TGF-β to adjust neuroinflammation in postoperative central inflammatory mice.

Topics: Animals; Apoptosis; Behavior, Animal; Bone Marrow Cells; Cell Differentiation; Cell Survival; Cognitive Dysfunction; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Inflammation; Lipopolysaccharides; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Neurons; Postoperative Period; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the life span. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor-β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology in rodents. Specifically, infusion of the serum protein albumin into the young rodent brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors or pharmacological inhibition of TGFβ signaling reversed these symptomatic outcomes in aged mice. Last, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging and demonstrates that the aging brain may retain considerable latent capacity, which can be revitalized by therapeutic inhibition of TGFβ signaling.

Topics: Adult; Aged; Aged, 80 and over; Aging; Albumins; Animals; Astrocytes; Blood-Brain Barrier; Chronic Disease; Cognitive Dysfunction; Gene Knockdown Techniques; Hippocampus; Humans; Mice, Transgenic; Middle Aged; Protein Kinase Inhibitors; Receptor, Transforming Growth Factor-beta Type I; Signal Transduction; Transforming Growth Factor beta; Young Adult

Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood-brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level.

Topics: Active Transport, Cell Nucleus; Amyloid beta-Peptides; Benzamides; Blood-Brain Barrier; Brain; Cell Line; Cognitive Dysfunction; Dioxoles; Dynamins; Endothelial Cells; HIV Infections; HIV-1; Humans; Hydrazones; Phosphorylation; Receptors, Transforming Growth Factor beta; RNA Interference; RNA, Small Interfering; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Vesicular Transport Proteins