Transformation of non-neuritic into neuritic plaques during AD progression drives cortical spread of tau pathology via regenerative failure.
Transformation of non-neuritic into neuritic plaques during AD progression drives cortical spread of tau pathology via regenerative failure.
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DOI：
10.1186/s40478-023-01688-6
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发表时间：
2023-12-01
影响因子：
7.1
通讯作者：
Prokop S
中科院分区：
文献类型：
--
作者：
Tsering W;Hery GP;Phillips JL;Lolo K;Bathe T;Villareal JA;Ruan IY;Prokop S
细胞外β淀粉样蛋白（Aβ）斑块和细胞内tau蛋白以神经元缠结（NFT）形式聚集是阿尔茨海默病（AD）的病理标志。这两种蛋白质聚集体在AD中如何相互作用的确切机制仍然是一个争论的问题。神经炎性斑块（NP）是Aβ斑块的一个亚类，含有营养不良性神经突（DN），被认为是AD所特有的，并可能在Aβ和tau的相互作用中发挥作用。对AD神经病理学改变（ADNC）严重程度增加的患者尸检脑标本中的NP和非NP进行定量，我们证明Aβ斑块和NP的总数增加，而非NP的数量停滞。此外，通过研究NP和NFT之间的相关性，我们在比较越来越严重的ADNC病例时发现了意想不到的脑区域特异性差异。在新皮质区NFT计数增加与NP计数在ADNC的进展过程中平行，而这种相关性在海马中没有观察到。这些数据支持的概念，非NP转化为NP在ADNC的进展，并表明NP可能驱动皮质NFT的形成。接下来，使用空间转录组学，我们分析了非NP和NP周围微环境的基因表达谱。我们确定了一个上调的神经元系统和钙依赖性事件通路周围NP相比，非NP。我们推测，这些转录的上调可能暗示在一个补偿机制的NP形成。我们的研究表明，非NP到NP的转化是ADNC进展中的关键事件，并指出再生失败是这一过程的潜在驱动力。在线版本包含补充材料，可通过10.1186/s40478-023-01688-6获得。
Extracellular amyloid-β (Aβ) plaques and intracellular aggregates of tau protein in form of neurofibrillary tangles (NFT) are pathological hallmarks of Alzheimer’s disease (AD). The exact mechanism how these two protein aggregates interact in AD is still a matter of debate. Neuritic plaques (NP), a subset of Aβ plaques containing dystrophic neurites (DN), are suggested to be unique to AD and might play a role in the interaction of Aβ and tau. Quantifying NP and non-NP in postmortem brain specimens from patients with increasing severity of AD neuropathological changes (ADNC), we demonstrate that the total number of Aβ plaques and NP increase, while the number of non-NP stagnates. Furthermore, investigating the correlation between NP and NFT, we identified unexpected brain region-specific differences when comparing cases with increasingly more severe ADNC. In neocortical regions NFT counts increase in parallel with NP counts during the progression of ADNC, while this correlation is not observed in hippocampus. These data support the notion that non-NP are transformed into NP during the progression of ADNC and indicate that NP might drive cortical NFT formation. Next, using spatial transcriptomics, we analyzed the gene expression profile of the microenvironment around non-NP and NP. We identified an upregulation of neuronal systems and Ca-dependent event pathways around NP compared to non-NP. We speculate that the upregulation of these transcripts may hint at a compensatory mechanism underlying NP formation. Our studies suggest that the transformation of non-NP to NP is a key event in ADNC progression and points to regenerative failure as a potential driving force of this process. The online version contains supplementary material available at 10.1186/s40478-023-01688-6.
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DOI：
10.1111/neup.12144
发表时间：
2015-02
期刊：
Neuropathology : official journal of the Japanese Society of Neuropathology
影响因子：
--
作者：
Kuninaka N;Kawaguchi M;Ogawa M;Sato A;Arima K;Murayama S;Saito Y
通讯作者：
Saito Y
影响因子：
5.5
作者：
通讯作者：
--
影响因子：
6.1
作者：
Boutajangout, A;Authelet, M;Brion, JP
通讯作者：
Brion, JP
影响因子：
--
作者：
Haroutunian, V;Perl, DP;Mohs, RC
通讯作者：
Mohs, RC
影响因子：
5.3
作者：
Dickson, TC;King, CE;Vickers, JC
通讯作者：
Vickers, JC