The Apolipoprotein E-ε4 allele (APOE-ε4) is the strongest genetic risk factor for late onset Alzheimer disease (AD). ApoE plays a critical role in amyloid-β (Aβ) accumulation in AD, and genetic deletion of the murine ApoE gene in mouse models results in a decrease or inhibition of Aβ deposition. The association between the presence of ApoE and amyloid in amyloidoses suggests a more general role for ApoE in the fibrillogenesis process. However, whether decreasing levels of ApoE would attenuate amyloid pathology in different amyloidoses has not been directly addressed. Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease characterized by the presence of widespread parenchymal and vascular Danish amyloid (ADan) deposition and neurofibrillary tangles. A transgenic mouse model for FDD (Tg-FDD) is characterized by parenchymal and vascular ADan deposition. To determine the effect of decreasing ApoE levels on ADan accumulation in vivo, we generated a mouse model by crossing Tg-FDD mice with ApoE KO mice (Tg-FDD^+/−/ApoE^−/−). Lack of ApoE results in inhibition of ADan deposition up to 18 months of age. Additionally, our results from a genetic screen of Tg-FDD^+/−/ApoE^−/− mice emphasize the significant role for ApoE in neurodegeneration in FDD via glial-mediated mechanisms. Taken together, our findings suggest that the interaction between ApoE and ADan plays a key role in FDD pathogenesis, in addition to the known role for ApoE in amyloid plaque formation in AD.

载脂蛋白 E-ε4 等位基因 (APOE-ε4) 是迟发性阿尔茨海默病 (AD) 的最强遗传风险因素。ApoE 在 AD 中的淀粉样蛋白-β (Aβ) 积累和小鼠ApoE的基因缺失中起关键作用小鼠模型中的基因导致 Aβ 沉积减少或抑制。淀粉样变性中 ApoE 的存在与淀粉样蛋白之间的关联表明 ApoE 在原纤维形成过程中具有更普遍的作用。然而，降低 ApoE 水平是否会减弱不同淀粉样变性中的淀粉样蛋白病理尚未得到直接解决。家族性丹麦痴呆 (FDD) 是一种常染色体显性遗传的神经退行性疾病，其特征是存在广泛的实质和血管丹麦淀粉样蛋白 (ADan) 沉积和神经原纤维缠结。FDD (Tg-FDD) 的转基因小鼠模型以实质和血管 ADan 沉积为特征。为了确定降低 ApoE 水平对体内 ADan 积累的影响，我们通过将 Tg-FDD 小鼠与ApoE KO 小鼠 (Tg-FDD ^+/- /ApoE ^-/- )。缺乏 ApoE 会导致 ADan 沉积受到抑制，直至 18 个月大。^{此外，我们对 Tg-FDD +/-} /ApoE ^-/-小鼠的遗传筛选结果强调了 ApoE通过神经胶质介导的机制在 FDD 神经变性中的重要作用。综上所述，我们的研究结果表明，ApoE 和 ADan 之间的相互作用在 FDD 发病机制中起着关键作用，此外 ApoE 在 AD 中淀粉样斑块形成中的已知作用除外。