y**********o 发帖数: 37 | 1 最近老板忽然对Alzheimer's disease产生极大的兴趣,非要把课题往这个方向上靠.我
研究了几篇综述后,有些最基本的问题想请教一下版上做这个方向的高人.相信这里应该
有很多前辈能够指导一下我这个外行,晚辈先在这里感谢一下所有回帖的.
问题一,目前市面上各种mouse models似乎都是转了human mutated genes,像APP,PS1什
么的.最常见的检测指标是A-beta和NFT的染色. 老鼠也有内源性的APP和Tau, 好象内源
性的Tau所形成的NFT在小鼠中一直无法诱导,那么内源性的APP可以经诱导产生A-beta斑
块吗? 公司能买到针对rodent的A-beta抗体, 说明有这种可能,只是主流的文章似乎都
在关注human gene product.有没有可能用老鼠内源性的APP来做疾病模型?
问题二,目前主流的观点对这个疾病的机理是否偏向于Ca overload? 我们手头现有的
mouse model显示reduced cytoplasmic Ca concentration,类似PSI/PS2 KO 模型,但这
个似乎无法被牵强的说成Alzheimer's disease model.
问题三,正常生理条件下也会产生一些A-beta,而且可能是soluble的.不知有没有人关注
过这些soluble的A-beta有何生理功能?
先想到了这些问题,后面还会有更多的疑问.谢谢各位高人给以解答! | n***w 发帖数: 2405 | 2 我不是这个领域的,读过一些AD的文章。我是这么想的:
1.因为用的是人的mutation,抗体用rodent raise,无所谓,用人的mutation就是为了
保证这个研究和临床的correlation。如果用rodent做,虽然表型一样,但是gene在
rodent上能成,但是在人上却不行,成不了大事。
2.我没有觉得主流觉得机制偏向Ca overload,这只是人们用来解释Abeta cascade的一
个思路。你找几个新的review来看看。
3.我觉得A beta产生就是要被cleaved,只是在哪里cleaved的问题。sAPP有paper说是
neurotrophic和neuroprotective作用的。 | h********r 发帖数: 519 | 3 现在最重点的是soluble ab oligomers, rather than ab fibrils or monomers, are the most toxic species. The origin of ab toxicity may come from the membrane-disruption. Ca overload may be consequence of membrane disruption due to the formation of ion channel. | n***w 发帖数: 2405 | 4 second this.
I learned this from two papers by Andrew Dillin.
are the most toxic species.
【在 h********r 的大作中提到】 : 现在最重点的是soluble ab oligomers, rather than ab fibrils or monomers, are the most toxic species. The origin of ab toxicity may come from the membrane-disruption. Ca overload may be consequence of membrane disruption due to the formation of ion channel.
| h*******o 发帖数: 4884 | 5 1) due to the intrinsic difference between rodent Abeta and human Abeta,
rodent Abeta do not form aggregates easily as human abeta.
For more detailed info, check "Charles G. Glabe" or Frank Laferla's paper.
As for NFT, most people in the field now agree that Tau is downstream of
Abeta.
2) Calcium and neurocytotoxicity hypothesis is quite old. It definitely has
its points but not the whole scheme.
3) Abeta is solube. The problem is Abeta oligomer. And the current opinion
is that soluble Abeta oligomer is the actual toxici species rather than
plaque. |
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