Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
J Cell Biol. 2011 Nov 28;195(5):765-79. doi: 10.1083/jcb.201105109. Epub 2011 Nov 21.
VPS35, a major component of the retromer complex, is important for endosome-to-Golgi retrieval of membrane proteins. Although implicated in Alzheimer's disease (AD), how VPS35 regulates AD-associated pathology is unknown. In this paper, we show that hemizygous deletion of Vps35 in the Tg2576 mouse model of AD led to earlier-onset AD-like phenotypes, including cognitive memory deficits, defective long-term potentiation, and impaired postsynaptic glutamatergic neurotransmission in young adult age. These deficits correlated well with an increase of β-amyloid peptide (Aβ) level in the mutant hippocampus. We further demonstrate that VPS35 is predominantly expressed in pyramidal neurons of young adult hippocampus and interacts with BACE1, a protease responsible for Aβ production. Loss of VPS35 function in the mouse hippocampus increased BACE1 activity. Suppression of VPS35 expression in culture decreased BACE1 trans-Golgi localization but enriched it in endosomes. These results demonstrate an essential role for VPS35 in suppression of AD neuropathology and in inhibition of BACE1 activation and Aβ production by promoting BACE1 endosome-to-Golgi retrieval.
VPS35 是回转体复合物的主要组成部分，对于内体到高尔基体的膜蛋白再循环非常重要。虽然与阿尔茨海默病（AD）有关，但 VPS35 如何调节 AD 相关的病理学尚不清楚。在本文中，我们表明 AD 的 Tg2576 小鼠模型中的 Vps35 半合子缺失导致早发性 AD 样表型，包括认知记忆缺陷、长时程增强缺陷和成年早期突触后谷氨酸能神经传递受损。这些缺陷与突变海马体中β-淀粉样肽 (Aβ) 水平的增加密切相关。我们进一步证明 VPS35 主要在成年海马体的锥体神经元中表达，并与 BACE1 相互作用，BACE1 是负责 Aβ产生的蛋白酶。在小鼠海马体中丧失 VPS35 功能会增加 BACE1 的活性。在培养物中抑制 VPS35 的表达会减少 BACE1 的反式高尔基体定位，但会使其在内体中富集。这些结果表明 VPS35 在抑制 AD 神经病理学和抑制 BACE1 激活和 Aβ 产生方面具有重要作用，其通过促进 BACE1 内体到高尔基体的再循环来实现。
