Suppressive Effects Of Amyloid β-Protein Fragment 31-35 On Late Phase Of Long-Term Potentiation: With Analyses Of Underlying Mechanisms

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, characterized mostly by cognitive deficits and progressive loss of memory. Amyloidβ(Aβ) protein, a 39～43 amino acid peptide derived by proteolysis of amyloid precursor protein, aggregates to form insoluble amyloid fibrils in senile plaques and plays a critical role in pathogenesis of AD. The neurotoxicity of Aβhas been widely reported. Some investigators have shown that soluble Aβmay impair learning and memory long before neurodegenerative changes that are characteristics of clinical AD. Therefore, one of the focuses on AD researches is to determine the causes of the mild cognitive impairment that usually presages the insidious onset of clinical dementia. Long-term potentiation (LTP) is a persistent enhancement of excitatory synaptic transmission induced by some kinds of preceding operations of high-frequency stimulation (HFS). The experiments with transgenic mice which highly expressed Aβin the brain show that the memory deficits are closely related to the impaired LTP in hippocampus. Thus, hippocampal LTP has long been thought to be suitable model for not only the study of synaptic plasticity but also the elucidation of mechanisms underlying cognitive and memory disorders, such as AD.Although the suppressive effects of Aβand its different soluble fragments on hippocampal LTP have been frequently reported, the mechanisms by which Aβimpairs LTP are unclear. Especially, most of these experiments have focused on the effects of Aβon the induction and maintenance of the short-term form of LTP or the early phase of LTP (E-LTP), while another kind of LTP, namely the long-lasting form of LTP or late phase of LTP (L-LTP) has recently been emphasized in literature. E-LTP is usually induced by a single HFS and lasts for approximately 1 h in vitro, and it is reportedly mediated by phosphorylation of existing proteins; in contrast, the hippocampal L-LTP is induced by multiple HFS and lasts for at least 3 h in vitro, and it is based on the new RNA transcription and protein synthesis. According to our knowledge, it is still unresolved about whether the maintenance of L-LTP might be affected by Aβand and its fragments, and if so, what mechanisms might be involved in.Therefore, the purposes of the present study were as follows: (1) clarifying the effects of two...