Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
VA San Diego Healthcare System, La Jolla, CA, USA.
J Alzheimers Dis. 2023;95(1):349-361. doi: 10.3233/JAD-230232.
Alzheimer's disease (AD) cases are often characterized by the pathological accumulation of α-synuclein (α-syn) in addition to amyloid-β (Aβ) and tau hallmarks. The role of α-syn has been extensively studied in synucleinopathy disorders, but less so in AD. Recent studies have shown that α-syn may also play a role in AD and its downregulation may be protective against the toxic effects of Aβ accumulation.
We hypothesized that selectively knocking down α-syn via RNA interference improves the neuropathological and biochemical findings in AD mice.
Here we used amyloid precursor protein transgenic (APP-Tg) mice to model AD and explore pathologic and behavioral phenotypes with knockdown of α-syn using RNA interference. We selectively reduced α-syn levels by stereotaxic bilateral injection of either LV-shRNA α-syn or LV-shRNA-luc (control) into the hippocampus of AD mice.
We found that downregulation of α-syn results in significant reduction in the number of Aβ plaques. In addition, mice treated with LV-shRNA α-syn had amelioration of abnormal microglial activation (Iba1) and astrocytosis (GFAP) phenotypes in AD mice.
Our data suggests a novel link between Aβ and α-syn pathology as well as a new therapeutic angle for targeting AD.
阿尔茨海默病（AD）患者的病理特征通常是除淀粉样蛋白-β（Aβ）和 tau 标志物外，还存在α-突触核蛋白（α-syn）的病理性积累。α-syn 在突触核蛋白病中的作用已被广泛研究，但在 AD 中研究较少。最近的研究表明，α-syn 可能也在 AD 中起作用，其下调可能对 Aβ 积累的毒性作用具有保护作用。
我们假设通过 RNA 干扰选择性敲低α-syn 可以改善 AD 小鼠的神经病理学和生物化学发现。
在这里，我们使用淀粉样前体蛋白转基因（APP-Tg）小鼠来模拟 AD，并使用 RNA 干扰探索 α-syn 的敲低与病理和行为表型的关系。我们通过立体定向双侧海马内注射 LV-shRNA α-syn 或 LV-shRNA-luc（对照），选择性地降低 AD 小鼠的α-syn 水平。
我们发现，下调α-syn 可导致 Aβ 斑块数量显著减少。此外，用 LV-shRNA α-syn 处理的小鼠在 AD 小鼠中改善了异常小胶质细胞激活（Iba1）和星形胶质细胞增生（GFAP）表型。
我们的数据表明 Aβ 和 α-syn 病理学之间存在新的联系，为靶向 AD 提供了新的治疗角度。
