2001 Fiscal Year Final Research Report Summary
Effects of membrane lipids on the incorporation of Alzheimer's β-amyloid protein into membranes and neurotoxicity
| Project/Area Number |
11672224
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | Tokyo Metropolitan Institute for Neuroscience |
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Principal Investigator |
KAWAHARA Masahiro Tokyo Metropolitan Institute for Neuroscience, 東京都神経科学総合研究所, 主事研究員 (40224828)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Alzheimer's disease / Prion disease / Parkinson's disease / calcium homeostasis / culture / development / cholesterol / membrane lipid |
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| Research Abstract |
It is widely accepted that the neurotoxicity of β-amyloid protein (AβP) is implicated in the etiology of Alzheimer's disease. We have previously shown that AβP is directly incorporated into membranes, forms cation-selective ion channels, and causes an increase in intracellular calcium levels of immortalized hypothalamic neurons. We hypothesize that the disruption of calcium homeostasis through the unregulated amyloid channels may be the primary event of neuro-toxicity of AβP. In this study, we investigated the detailed characteristics of the increase in intracellular calcium levels of primary cultured rat hippocampal neurons caused by AβP using a multisite fluorometry system. We found and report here that AβP caused a marked increase in intracellular calcium levels of long-term (more than three weeks)-cultured rat hippocampal neurons, but not in short-term (less than 2 weeks)-cultured neurons. The responses of neurons to AβP were highly heterogeneous. Immunohistochemical observation revealed that some restricted neurons have an affinity to the AP. To determine the substances that can confer protection against the neurotoxicity of AβP, we preadministerated dehydroepiandrosterone sul-phate (DHEA-S), whose levels in the serum of elderly are reduced, and found a significant inhibition of the increase in intracellular calcium levels induced by AβP. Our results suggest the implication of the ability of AβP to form amyloid channels may be based on the Alzheimer's pathogenesis. It is also possible that the endogenous substances such as DHEA-S may con-tribute to the prevention from the neurotoxicity of AβP.
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