NF-κB Activiation Induced By β-amyloid In Hippocampus Of Rats And Pharmaceutical Prevention

Alzheimer's disease (AD) is a degenerative neuropathy characterized by progressive dementia. Its pathological features are extracellular senile plaque (SP) formed by the deposition of theβ-amyloid (Aβ), degenerating neurons, neurofilament tangle (NFT) and and the presence of numerous activated astrocytes and microglia and. All of the pathological changes are related to Aβ according to the recent notion and glial activation as well as the immune and inflammatory response are invoved in the pathogenesis of Alzheimer disease. But the molecular mechanisms underlying its effects on glia and the relationship between glial activation and neuronal death are not well defined. Recently, most studies of postmortem brain tissue from patiets with Alzheimer disease or primary culture of neuronal cells in vitro have revealed the relationship between NF-κB activation and Aβ neurotoxity, but little was done in vivo. We used the animal model of AD by stereotaxic damage of CA1 area of right rat hippocampus using aggressive Aβ25-35 in this experiment. The changes of their memory and the hippocampus pathological abnormalities were observed and NF-κB can be stimulated in neural cells by Aβ. We explore the relationship between the NF-κB activation and Aβ neurotoxity. At the same time, we observed the prevention of Vitamin E to the Aβ-injured rats, try to explain its preventive mechanism and provide the experimental evidence for the Vitamin E used in clinics. Ⅰ. The establishment of the rat model of hippocampal CA1 region damage by Aβ. Aβis the core of SP, which is the major pathological feature of AD, and related to the other pathological hallmark such as NFT, degenerating neurons and glial activation; The hippocampus is the most vulnerable area, and is highly related to the ability of study and memory, especially recent memory. In the early stage of Alzheimer disease, there are a lot of NFTs and neurons loss before the pathological changes were observed in the cortex. So the rat model of hippocampal CA1 region damage by Aβ is a good choice to study the pathological and behavioral changes in AD. We stereotaxically damaged hippocampal CA1 region (3.0mm behind the anterior fontanelle, 2.0mm to the right of the sagittal suture, 2.6mm under the dura mater) of AD rat using Aβ25-35 according to "The stereotaxic atlas of rat brain", and observed the changes of memory using morris test and the hippocampus pathological abnornalities. The results showed: (1) The model had such advantages as exact localization, high success rate, and good repetition, etc. (2) morris test: AD rat showed significant decreases in the time of memory recovery (p<0.05). (3) Mild gliosis could be seen beside the needle trace in the saline group, there were not neuronal apoptosis in the cortex and hippocampus with HE staining. Meanwhile, in the Aβgroup, the neuron number in hippocampus was smaller than in the saline group, the degenerated neurons and gliosis were seen and there were few solitary shrunken neurons in hippocampus. The results suggested: we have successfully established the rat model of hippocampal CA1 region damaged by Aβ, which partly imitated the behavioral and pathological changes of Alzheimer disease, such as the memory dysfunction, the deposition of Aβ and neuron loss etc. It provides the condition easy to control in space and time in studying the mechanism and of damage induced by Aβ in vivo, and is a satisfactory model directed against the mechaniam of Aβ neurotoxity and its pharmaceutical therapy. Ⅱ. The relationship between NF-κB activation and Aβ neurotoxity.Aβ, a 39-43 amino acid fragment derived from β-amyloid precursor protain(βAPP), forms insoluble fibrillar aggregates that have been linked to neuronal and vascular degeneration in AD brains. It is neurotoxic and its overexpresssion or deposition in brains is seen as the reason of degeneration in nervous system of AD patients. However, deposition of Aβ by itself is not sufficient to produce the AD clinical syndrome...