Neuroactive Molecules in the Brains of Nonhuman Primates and Their Therapeutic Application to Neurodegenerative Disorders

霊長類脳内の神経活性分子とそれらの神経疾患治療への応用

Motoharu Hayashi

　ヒトを含む霊長類の中枢神経系は、他の哺乳類に比べより複雑である。特に視覚野や前頭、頭頂、側頭各連合野が拡大している。この拡大は霊長類に高い視覚能力や学習能力を与えている。また発達期のマカク大脳皮質では軸索やシナプスの一過性の増加という特異的な現象が起こる。我々はこれらの発達現象に関わる分子として成長関連タンパク質、GAP43、SCG10と神経栄養因子のBDNFとレセプターTrkBに注目してきた。その結果、シグナルを伝達しないTrkB分子種がGAP43とSCG10の遺伝子発現を阻害し軸索の除去が起こること、またBDNFがシナプス形成に関与する可能性を示した。一方加齢過程では、脳内におけるBDNFやソマトスタチン遺伝子発現の低下とアミロイドペプチドの出現が観察された。同様の現象はアルツハイマー病患者脳でも観察され、老齢ザルは本疾患発症のメカニズム解明に重要なモデル動物と考えられる。さらに将来アルツハイマー病、パーキンソン氏病、ハンチントン舞踏病や統合失調症等の神経疾患の治療に、各種神経栄養因子類の遺伝子導入が有効である可能性があり、現在までに行われてきたマカクザルを用いた基礎研究を紹介した。

Central Nervous System Agents in Medicinal Chemistry 8, 220-228. (2008)

The central nervous system (CNS) is more complex in primates, including humans, than in other mammals. Primates have particularly larger, visual, prefrontal, parietal, and temporal cortices. This expansion may cause the higher visual and learning abilities. Furthermore, transient increases in axons and synapses are unique characteristics in the primate neocortex during development. To understand these processes from the molecular level, we have focused on growth-associated proteins, GAP-43 and SCG-10 and on neurotrophins such as BDNF and its TrkB receptor. We have found that the development of truncated TrkB, which lacks the tyrosine kinase domain, correlated well with the downregulation of GAP-43 and SCG-10 expression. This downregulation seems to result in the elimination of axons in primate neocortices during development. The highest levels of BDNF protein in the primate visual and prefrontal cortices occur between 1 and 6 months of age, when the number of synapses is highest, suggesting that BDNF is a candidate molecule for the development of synapses in the primate neocortex. In aging primates, expression of BDNF and somatotstatin (SRIF) decreased and Aβpeptides accumulated. Similar cellular and molecular changes have been found in the brains of patients with Alzheimer’s disease, suggesting that aged monkeys are good model animals for this disease. Furthermore, gene therapies for various neurotrophins may be used in the future to cure neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and schizophrenia.

Copyright(C) 2008 PRI ().