Rac1b Increases with Progressive Tau Pathology within Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease
Rac1b Increases with Progressive Tau Pathology within Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease
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DOI：
10.1016/j.ajpath.2011.10.027
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发表时间：
2012-02-01
影响因子：
6
通讯作者：
Mufson, Elliott J.
中科院分区：
文献类型：
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作者：
Perez, Sylvia E.;Getova, Damianka P.;Mufson, Elliott J.
胆碱能基底前脑（CBF）基底核（NB）神经元在阿尔茨海默病（AD）进展过程中显示神经原纤维缠结（nft），但这种选择性易感性的机制目前尚不清楚。Rac1是gtpase Rho家族的一员，可能与促凋亡泛神经营养因子受体p75（NTR）相互作用，诱导AD NB神经元细胞骨架异常。在此，我们检测了在AD进展过程中NB胆碱能神经元中Rac1b （Rac1的一种组成型活性剪接变体）的表达。从临床诊断为无认知障碍（NCI）、轻度认知障碍或AD的死亡患者身上采集的CBF组织被免疫标记为p75（NTR）和Rac1b。在p75（NTR）阳性的NB神经元中，Rac1b以细胞质弥散颗粒、松散聚集的细丝或致密球体的形式出现。尽管Rac1b与tau细胞骨架标记物共定位，但与轻度认知障碍和NCI相比，仅在AD中表达Rac1b的p75（NTR）免疫反应神经元的百分比显着增加。此外，使用定制芯片的单细胞基因表达谱显示，与NCI中rac1b阳性/p75（NTR）阳性的核周细胞相比，AD中rac1b阳性/p75（NTR）标记的NB神经元中小窝蛋白2、GNB4和脂肪酶A的表达下调。这些蛋白参与了Rac1通路/细胞周期进程和脂质代谢。这些数据表明，在阿尔茨海默病的CBF NB神经元亚群中，Rac1b的表达作为各种信号通路的调节剂或换能器，导致NFT形成和膜功能障碍。（中国病理杂志，2012,180:526-540;DOI: 10.1016/ j.j ajpath.2011.10.027）
Cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons display neurofibrillary tangles (NFTs) during Alzheimer's disease (AD) progression, yet the mechanisms underlying this selective vulnerability are currently unclear. Rac1, a member of the Rho family of GTPases, may interact with the proapoptotic pan-neurotrophin receptor p75(NTR) to induce neuronal cytoskeletal abnormalities in AD NB neurons. Herein, we examined the expression of Rac1b, a constitutively active splice variant of Rac1, in NB cholinergic neurons during AD progression. CBF tissues harvested from people who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75(NTR) and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75(NTR)-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75(NTR)-immunoreactive neurons expressing Rac1b was significantly increased only in AD compared with both mild cognitive impairment and NCI. Furthermore, single-cell gene expression profiling with custom-designed microarrays showed down-regulation of caveolin 2, GNB4, and lipase A in AD Rac1b-positive/p75(NTR)-labeled NB neurons compared with Rac1b-negative/p75(NTR)- positive perikarya in NCI. These proteins are involved in Rac1 pathway/cell cycle progression and lipid metabolism. These data suggest that Rac1b expression acts as a modulator or transducer of various signaling pathways that lead to NFT formation and membrane dysfunction in a subgroup of CBF NB neurons in AD. (Am J Pathol 2012, 180:526-540; DOI: 10.1016/j.ajpath.2011.10.027)