Convergence Research Center for Diagnosis Treatment Care of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
Department of Integrated Biomedical and Life Science, Korea University, Seoul, 02708, Republic of Korea.
Sci Rep. 2019 Oct 29;9(1):15557. doi: 10.1038/s41598-019-51914-2.
Emerging evidences suggest that phospholipid metabolism is altered in Alzheimer's disease (AD), but molecular mechanisms on how this affects neurodegeneration in AD is poorly understood. SHIP2 is a phosphoinositide-metabolizing enzyme, which dephosphorylates PI(3,4,5)P resulting to PI(3,4)P, and it has been recently shown that Aβ directly increases the activity of SHIP2. Here we monitored, utilizing fluorescent SHIP2 biosensor, real-time increase of PI(3,4)P-containing vesicles in HT22 cells treated with Aβ. Interestingly, PI(3,4)P is accumulated at late endosomes and lysosomal vesicles. We further discovered that ARAP3 can be attracted to PI(3,4)P-positive mature endosomes via its PH domain and this facilitates the degradation of ARAP3. The reduced level of ARAP3 then causes RhoA hyperactivation and filamentous actin, which are critical for neurodegeneration in AD. These results provide a novel molecular link between Aβ and actin disruption through dysregulated phosphoinositide metabolism, and the SHIP2-PI(3,4)P-ARAP3-RhoA signaling pathway can be considered as new therapeutic targets for synaptic dysfunctions in Alzheimer's disease.
新出现的证据表明，阿尔茨海默病（AD）中磷脂代谢发生改变，但尚不清楚这如何影响 AD 中的神经退行性变的分子机制。SHIP2 是一种磷酸肌醇代谢酶，可使 PI(3,4,5)P 去磷酸化生成 PI(3,4)P，最近的研究表明 Aβ 可直接增加 SHIP2 的活性。在这里，我们利用荧光 SHIP2 生物传感器监测到 Aβ 处理的 HT22 细胞中含有 PI(3,4)P 的囊泡实时增加。有趣的是，PI(3,4)P 积累在晚期内体和溶酶体囊泡中。我们进一步发现，ARAP3 可以通过其 PH 结构域被吸引到 PI(3,4)P 阳性成熟内体上，从而促进 ARAP3 的降解。ARAP3 水平降低会导致 RhoA 过度激活和丝状肌动蛋白形成，这对 AD 中的神经退行性变至关重要。这些结果提供了 Aβ 和肌动蛋白破坏之间通过失调的磷酸肌醇代谢的新的分子联系，SHIP2-PI(3,4)P-ARAP3-RhoA 信号通路可被视为阿尔茨海默病中突触功能障碍的新治疗靶点。
