Targeting increased levels of APP in Down syndrome: Posiphen-mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model.
Targeting increased levels of APP in Down syndrome: Posiphen-mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model.
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靶向唐氏综合症的APP水平增加：POSIPHEN介导的APP及其产品的降低及其产品在TS65DN小鼠模型中反向内体表型。
DOI：
10.1002/alz.12185
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Mobley WC
中科院分区：
文献类型：
--
作者：
Chen XQ;Salehi A;Pearn ML;Overk C;Nguyen PD;Kleschevnikov AM;Maccecchini M;Mobley WC
最近针对阿尔茨海默病（AD）中的淀粉样蛋白β（A β）和tau的临床试验尚未证明疗效。回顾AD发病机制的假设，并确定它们之间可能的联系，可以提高上游启动事件和下游机制的见解，从而促进新的治疗方法的发现。在唐氏综合征（DS）中，一个明显倾向于发展早发性AD的人群，增加APP基因剂量对于AD神经病理学和痴呆都是必要的，这一证据表明淀粉样前体蛋白（APP）及其产物水平的正常化是进一步确定AD发病机制和发现新治疗方法的一种途径。AD和DS共有几种特征性表现。DS由21号染色体的全部或部分三体性引起;该染色体含有约233个蛋白质编码基因，包括APP。最近的证据表明APP及其99个氨基酸C末端片段（C99，也称为β-CTF）的基因表达增加在内体/溶酶体系统失调中起决定性作用。后者对正常细胞功能和神经元中传递神经营养信号至关重要。我们假设DS中APP基因剂量的增加启动了一个过程，其中全长APP（fl ‐ APP）及其产物（包括β ‐ CTF和可能的A β肽（A β 42和A β 40））水平的增加通过内体依赖性机制驱动AD发病机制，这损害了神经营养信号的转运。为了验证这一假设，我们在DS的Ts65Dn小鼠模型中进行了研究，并检查了Posiphen的作用，Posiphen是一种口服小分子，在先前的研究中显示可以减少fl ‐ APP。在体外，Posiphen降低了fl ‐ APP及其C末端片段，逆转了Rab5的过度激活和早期内体扩大，并恢复了神经营养因子信号的逆行转运。在体内，Posiphen处理（50 mg/kg/d，26天，腹膜内[i.p.]）Ts65Dn小鼠的耐受性良好，并且没有表现出对行为的不良影响。给药导致fl-APP、C-末端片段水平正常化，A β物质小幅减少，Rab5活性恢复至正常水平，磷酸化tau（p-tau）减少，Trk B（原肌球蛋白受体激酶B）活化和Akt（蛋白激酶B [PKB]）、ERK（细胞外信号调节激酶）和CREB（cAMP反应元件结合蛋白）信号通路缺陷逆转。值得注意的是，Posiphen处理还将胆碱乙酰转移酶蛋白的水平恢复到2N水平。这些发现支持APP基因剂量假说，指出需要进行额外的研究，以探索APP基因表达增加增加DS中AD风险的机制，并可能利用治疗使APP及其产物水平正常化，以预防DS患者的AD。重要的未回答的问题是：（1）何时应该干预DS患者;（2）基于APP的策略是否会对长期增加APP基因剂量诱导的可能适应性变化产生不良后果;（3）21号染色体上或DS中表达失调的其他染色体上的其他基因是否有助于AD发病机制;和（4）可以将基于APP的治疗与针对其他AD表型（包括p-tau和炎症）的治疗结合使用的联合收割机的模型策略。APP基因剂量假说与AD的淀粉样蛋白级联假说以及支持其的遗传和细胞生物学观察相互作用。此外，fl ‐ APP蛋白和产物的上调可能驱动下游事件，这些事件使tau稳态和炎症反应失调，从而导致AD发病机制的传播。
Recent clinical trials targeting amyloid beta (Aβ) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments. AD and DS share several characteristic manifestations. DS is caused by trisomy of whole or part of chromosome 21; this chromosome contains about 233 protein‐coding genes, including APP. Recent evidence points to a defining role for increased expression of the gene for APP and for its 99 amino acid C‐terminal fragment (C99, also known as β‐CTF) in dysregulating the endosomal/lysosomal system. The latter is critical for normal cellular function and in neurons for transmitting neurotrophic signals. We hypothesize that the increase in APP gene dose in DS initiates a process in which increased levels of full‐length APP (fl‐APP) and its products, including β‐CTF and possibly Aβ peptides (Aβ42 and Aβ40), drive AD pathogenesis through an endosome‐dependent mechanism(s), which compromises transport of neurotrophic signals. To test this hypothesis, we carried out studies in the Ts65Dn mouse model of DS and examined the effects of Posiphen, an orally available small molecule shown in prior studies to reduce fl‐APP. In vitro, Posiphen lowered fl‐APP and its C‐terminal fragments, reversed Rab5 hyperactivation and early endosome enlargement, and restored retrograde transport of neurotrophin signaling. In vivo, Posiphen treatment (50 mg/kg/d, 26 days, intraperitoneal [i.p.]) of Ts65Dn mice was well tolerated and demonstrated no adverse effects in behavior. Treatment resulted in normalization of the levels of fl‐APP, C‐terminal fragments and small reductions in Aβ species, restoration to normal levels of Rab5 activity, reduced phosphorylated tau (p‐tau), and reversed deficits in TrkB (tropomyosin receptor kinase B) activation and in the Akt (protein kinase B [PKB]), ERK (extracellular signal‐regulated kinase), and CREB (cAMP response element–binding protein) signaling pathways. Remarkably, Posiphen treatment also restored the level of choline acetyltransferase protein to 2N levels. These findings support the APP gene dose hypothesis, point to the need for additional studies to explore the mechanisms by which increased APP gene expression acts to increase the risk for AD in DS, and to possible utility of treatments to normalize the levels of APP and its products for preventing AD in those with DS. Important unanswered questions are: (1) When should one intervene in those with DS; (2) would an APP‐based strategy have untoward consequences on possible adaptive changes induced by chronically increased APP gene dose; (3) do other genes present on chromosome 21, or on other chromosomes whose expression is dysregulated in DS, contribute to AD pathogenesis; and (4) can one model strategies that combine the use of an APP‐based treatment with those directed at other AD phenotypes including p‐tau and inflammation. The APP gene dose hypothesis interfaces with the amyloid cascade hypothesis of AD as well as with the genetic and cell biological observations that support it. Moreover, upregulation of fl‐APP protein and products may drive downstream events that dysregulate tau homeostasis and inflammatory responses that contribute to propagation of AD pathogenesis.
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影响因子：
11
作者：
Alić I;Goh PA;Murray A;Portelius E;Gkanatsiou E;Gough G;Mok KY;Koschut D;Brunmeir R;Yeap YJ;O'Brien NL;Groet J;Shao X;Havlicek S;Dunn NR;Kvartsberg H;Brinkmalm G;Hithersay R;Startin C;Hamburg S;Phillips M;Pervushin K;Turmaine M;Wallon D;Rovelet-Lecrux A;Soininen H;Volpi E;Martin JE;Foo JN;Becker DL;Rostagno A;Ghiso J;Krsnik Ž;Šimić G;Kostović I;Mitrečić D;LonDownS Consortium;Francis PT;Blennow K;Strydom A;Hardy J;Zetterberg H;Nižetić D
通讯作者：
Nižetić D
DOI：
10.3233/jad-179941
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
通讯作者：
Klein WL
影响因子：
7.4
作者：
Chen XQ;Sawa M;Mobley WC
通讯作者：
Mobley WC
影响因子：
11
作者：
Chopra N;Wang R;Maloney B;Nho K;Beck JS;Pourshafie N;Niculescu A;Saykin AJ;Rinaldi C;Counts SE;Lahiri DK
通讯作者：
Lahiri DK
影响因子：
16.1
作者：
Banks, William A.
通讯作者：
Banks, William A.