Van Broeck Bianca, Vanhoutte Greet, Pirici Daniel, Van Dam Debby, Wils Hans, Cuijt Ivy, Vennekens Krist'l, Zabielski Monika, Michalik Andrej, Theuns Jessie, De Deyn Peter Paul, Van der Linden Annemie, Van Broeckhoven Christine, Kumar-Singh Samir
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, BE-2610 Antwerpen, Belgium.
Neurobiol Aging. 2008 Feb;29(2):241-52. doi: 10.1016/j.neurobiolaging.2006.10.016. Epub 2006 Nov 16.
Transgenic mouse models of Alzheimer's disease (AD) expressing high levels of amyloid precursor protein (APP) with familial AD (FAD) mutations have proven to be extremely useful in understanding pathogenic processes of AD especially those that involve amyloidogenesis. We earlier described Austrian APP T714I pathology that leads to one of the earliest AD age-at-onsets with abundant intracellular and extracellular amyloid deposits in brain. The latter strikingly was non-fibrillar diffuse amyloid, composed of N-truncated A beta 42 in absence of A beta 40. In vitro, this mutation leads to one of the highest A beta 42/A beta 40 ratios among all FAD mutations. We generated an APP T714I transgenic mouse model that despite having 10 times lower transgene than endogenous murine APP deposited intraneuronal A beta in brain by 6 months of age. Accumulations increased with age, and this was paralleled by decreased brain sizes on volumetric MRI, compared to age-matched and similar transgene-expressing APP wild-type mice, although, with these levels of transgenic expression we did not detect neuronal loss or significant memory impairment. Immunohistochemical studies revealed that the majority of the intraneuronal A beta deposits colocalized with late endosomal markers, although some A beta inclusions were also positive for lysosomal and Golgi markers. These data support earlier observations of A beta accumulation in the endosomal-lysosomal pathway and the hypothesis that intraneuronal accumulation of A beta could be an important factor in the AD pathogenesis.
表达具有家族性阿尔茨海默病（FAD）突变的高水平淀粉样前体蛋白（APP）的阿尔茨海默病（AD）转基因小鼠模型已被证明在理解AD的致病过程中非常有用，尤其是那些涉及淀粉样蛋白生成的过程。我们之前描述了奥地利APP T714I病理学，它导致最早的AD发病年龄之一，脑内有大量细胞内和细胞外淀粉样沉积物。后者显著的是无纤维的弥漫性淀粉样蛋白，由不含Aβ40的N端截短的Aβ42组成。在体外，这种突变导致所有FAD突变中最高的Aβ42/Aβ40比率之一。我们生成了一个APP T714I转基因小鼠模型，尽管其转基因水平比内源性小鼠APP低10倍，但在6个月大时脑内神经元内沉积了Aβ。积累随年龄增加，与年龄匹配且表达相似转基因的APP野生型小鼠相比，体积MRI显示脑尺寸减小与之平行，尽管在这些转基因表达水平下我们未检测到神经元丢失或明显的记忆损害。免疫组织化学研究表明，大多数神经元内Aβ沉积物与晚期内体标记物共定位，尽管一些Aβ包涵体也对溶酶体和高尔基体标记物呈阳性。这些数据支持了早期关于Aβ在内体-溶酶体途径中积累的观察结果以及Aβ在神经元内积累可能是AD发病机制中一个重要因素的假说。
