Department of Psychology, Stony Brook University, Stony Brook, NY, USA.
J Alzheimers Dis. 2014;38(3):621-32. doi: 10.3233/JAD-130758.
Alzheimer's disease (AD) is an age-dependent neurodegenerative condition that causes a progressive decline in cognitive function. Accumulation of amyloid β-protein (Aβ) in the brain is a prominent feature of AD and related disorders. However, the levels of Aβ accumulation alone are not a reliable predictor of cognitive deficits. Aβ accumulates in AD brain in the form of parenchymal amyloid plaques and cerebral vascular deposits. Although both types of lesions can contribute to cognitive decline, their temporal impact remains unclear. Moreover, cerebral microvascular pathology is identified as an early driver of cognitive impairment. Here for the first time, we compared two transgenic mouse strains, Tg-5xFAD and Tg-SwDI, which exhibit similar onset and anatomical accumulation of Aβ, but with distinct parenchymal and microvascular compartmental deposition, respectively, to assess their impact on cognitive impairment. Cohorts of each line were tested at 3 and 6 months of age to assess the relationship between spatial working memory performance and quantitative pathology. At 3 months of age, Tg-SwDI mice with onset of cerebral microvascular amyloid were behaviorally impaired, while the Tg-5xFAD, which had disproportionately higher levels of total Aβ, soluble oligomeric Aβ, and parenchymal amyloid were not. However, at 6 months of age, behavioral deficits for both groups of transgenic mice were evident, as the levels of Aβ pathologies in the Tg-5xFAD accumulated to extremely high amounts. The present findings suggest early-onset cerebral microvascular amyloid deposition, that precedes high parenchymal levels of Aβ, may be an important early factor in the development of cognitive deficits.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，可导致认知功能进行性下降。大脑中淀粉样β-蛋白（Aβ）的积累是 AD 及相关疾病的一个显著特征。然而，Aβ的积累水平本身并不能可靠地预测认知缺陷。Aβ在 AD 大脑中以实质淀粉样斑块和脑血管沉积物的形式积累。尽管这两种病变都可能导致认知能力下降，但它们的时间影响尚不清楚。此外，脑微血管病理学被认为是认知障碍的早期驱动因素。在这里，我们首次比较了两种转基因小鼠品系，Tg-5xFAD 和 Tg-SwDI，它们表现出相似的 Aβ起始和解剖积累，但分别具有不同的实质和微血管隔室沉积，以评估它们对认知障碍的影响。每条线的队列在 3 个月和 6 个月大时进行测试，以评估空间工作记忆表现与定量病理学之间的关系。在 3 个月大时，具有脑微血管淀粉样蛋白起始的 Tg-SwDI 小鼠行为受损，而 Tg-5xFAD 则没有，因为 Tg-5xFAD 具有不成比例高的总 Aβ、可溶性寡聚 Aβ和实质淀粉样蛋白。然而，在 6 个月大时，两种转基因小鼠的行为缺陷都很明显，因为 Tg-5xFAD 中的 Aβ病理水平积累到极高的水平。本研究结果表明，早发性脑微血管淀粉样蛋白沉积，先于高水平的实质 Aβ，可能是认知缺陷发展的一个重要早期因素。
