Effects of TGF-β1 on the aβ-40 and α- β- γ secretase expression in prefrontal cortex and hippocampus of experimental alzheimer's diseases

Alzheimer's disease (AD) is a chronic complex neurodegenerative disease characterized by impaired learning and memory functions and regression in activities of daily living. Amyloid plaques, neurofibrillary tangle formation, loss of neurons and synapses, and marked atrophy in the brain are the most important histopathological findings of the disease. Although many factors related to the etiology, pathogenesis and histopathology of the disease have been suggested to date, the exact mechanism is not yet known. Amyloid beta (Aβ) deposition is the most fundamental change responsible for the pathogenesis of the disease. Aβ-40 and Aβ-42 are important amyloid beta species in the pathogenesis. Amyloid plaque formation occurs with abnormal cleavage of amyloid precursor protein (APP) as a result of hyperactivation of β-secretase and γ-secretase enzymes. Transforming growth factor β1 (TGF-β1) is an important growth factor with critical roles in cell metabolism, tissue homeostasis, neuronal development and synaptic plasticity. It has been suggested that TGF-β1 may be beneficial in preventing the formation and progression of neurodegenerative diseases with its anti-inflammatory effect. TGF-β1 has been shown to have neuroprotective effects in conditions of excitotoxicity, ischemia, and hypoxia. In aging and chronic inflammation, inactivation of TGF-β1/Smad signaling induces microglia-mediated neurodegeneration. Thus, regulation of TGF-β1 signaling may be a new pharmacological strategy in the treatment of AD. Although there are studies showing the neuroprotective effect of TGF-β1 in the literature, no study has been found on the effect of TGF-β1 on secretase enzymes, which have an active role in Aβ accumulation in Alzheimer's disease. In this study, it was aimed to examine the effect of TGF-β1 on the regulation of α, β and γ-secretase enzymes, Aβ-40 accumulation, apoptosis and neuronal damage in an experimental AD-like disease model. Eighty-eight male Swiss-Albino mice were randomly divided into 5 groups as the control group without any treatment, the sham group in which only SF was applied, the group in which TGF-β was administered, the experimental group in which Scopolamine was applied for 28 days, and the treatment group in which Scopolamine + TGF-β1 was applied. The mice in the treatment group were also divided into 2 subgroups. In order to examine the long-term effects of the applied methods, sham, TGF-β1 control, experiment, treatment-1 and treatment-2 groups were followed until the 56th day, and the Moris water pool test was applied on the 28th and 56th days, and memory functions were examined. Hippocampus and prefrontal cortex tissues taken from all groups on the 28th and 56th days were examined by light and electron microscopic, immunohistochemical and biochemical methods. In the Moris water pool test, it was observed that memory performance decreased in the experimental groups, while memory performance increased again in the treatment groups. It was observed that Aβ-40 and caspase-3 immunoreactivity increased in the hippocampus and prefrontal cortex on the 28th and 56th days in the experimental group, and immunoreactivity was decreased as a result of TGF-β1 treatment. Structural changes were detected in neurons and gliyal cells in the experimental groups in light and electron microscopic examinations. It was interesting that cellular changes were relatively decreased in TGF-β1 treatment groups. It was found that α-secretase expression decreased in the experimental groups, while it increased in the treatment groups. It was determined that β and γ-secretase enzyme levels increased in the experimental groups and decreased in the treatment groups. It was thought that TGF-β1 might have a therapeutic effect on Alzheimer's disease by increasing memory performance and preventing Aβ-40 accumulation in the Alzheimer's-like disease model induced by scopolamine. In addition, it was determined that it may be effective in preventing neuronal damage by down-regulating caspase-3 expression. At the same time, it has been shown that it can be effective in preventing the disease with its regulatory role on α, β and γ-secretase enzymes. When all the findings were evaluated together, it was concluded that TGF-β1 could be evaluated as a therapeutic agent in Alzheimer's disease.