老年痴呆と細胞骨格タンパク質

Senile dementia and cytoskeletal proteins.

はじめに

　Alzheimer病，Creutzfeldt-Jakob病，Kuru病などの痴呆を呈する神経疾患においては，神経病理学的特徴として，老人斑（senile plaques），神経原線維変化（neurofibrillary tangles）およびアミロイド沈着血管などが見出される。これらの変性組織には電子顕微鏡を用いて観察すると線維構造がみられることから，神経細胞の細胞骨格を作っている線維，すなわち微小管（microtubules），ニューロフィラメント（neurofilament）あるいはアクチン線維などがなんらかの変性を受けてできたのではないかと当初は予測されていた。

　これらの難溶性の変性線維に関する生化学的研究は，ここ数年の間にめざましい進歩がみられ，神経原線維変化は微小管やニューロフィラメントの主要構成タンパク質よりも，微量に含まれる付属タンパク質，すなわちMAPs（microtubule associated proteins）の一つであるタウ（τ）という因子のほうが重要な成分であることが明らかになってきた。

Senile plaques, neurofibrillary tangles and amyloid congophilic angiopathy are neuropathological features characteristic of neurodegenerative diseases which present dementia such as Alzheimer's disease, Creutzfeldt-Jakob disease and Kuru disease. In these degenerating changes, fibrous structures were observed by electron microscope. Fibers of neurofibrillary tangles have been referred to as paired helical filaments (PHF). But, recent observation of purified PHF by negative staining method with high power electron microscope has revealed that PHF are composed of two layers of four parallel subunits, and they twist like ribbon or tape. On the other hand, fibers of senile plaques and amyloid congophilic angiopathy are 6~7 nm in diameter and 200~300 nm in length which belong to amyloid fibers. Fine structure of amyloid fibers was revealed to be tubular with six components in a circle by freeze fracture method. Fine structures of these degenerating fibers are different from those of cytoskeletal filaments such as microtubules, neurofilaments and actin filaments. Then, the relationships between these degenerating fibers and normal cytoskeletal fibers were investigated by comparison of biochemical and immunological properties. The insolubility of these degenerating fibers has been stumbling brock to isolation and biochemical study. But, recently, PHF and amyloid fibers were purified and solubilized by high concentration of formic acid. From SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) and immunological studies (immunoblotting and immunohistochemistry) of solubilized protein of PHF, it was estimated that main components of PHF is phosphorylated tau factor of microtubule-associated proteins (MAPs). While, polypeptides with the molecular weight of 4 kDa were isolated from amyloid fibers and referred to as β-protein or A 4 protein. The amino acid sequence of this polypeptide was determined and cDNA encoding the precursor of β-protein was cloned. From the nucleotide sequence of cDNA, it is estimated that the precursor of β-protein belong to membrane receptor protein which includes serine protease inhibitor region. These results suggest that disorder in regulation of synthesis of some cytoskeletal proteins and their degradation will be the formation mechanism of PHF and amyloid fibers.