阿尔茨海默病 APP 基因敲入小鼠模型中，脑内 Aβ 沉积先于脑脊液和血清 Aβ42/Aβ40 比值降低。

Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App knock-in mouse model of Alzheimer's disease.

机构信息

Clinical Memory Research Unit, Lund University, 22184, Lund, Sweden.

Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

出版信息

Alzheimers Res Ther. 2023 Mar 25;15(1):64. doi: 10.1186/s13195-023-01196-8.

DOI:10.1186/s13195-023-01196-8

PMID:36964585

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10039589/

Abstract

BACKGROUND

Aβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer's disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD.

METHODS

CSF, serum, and brain tissue were collected from 3- to 18-month-old App knock-in mice (n = 48) and 2-18-month-old App knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay.

RESULTS

In App knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in App knock-in mice during the observation time.

CONCLUSIONS

Our findings suggest a temporal sequence of events in App knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum.

摘要

背景

在临床前阿尔茨海默病（AD）中，脑脊液（CSF）和血液中的 Aβ42/Aβ40 比值降低，但它们与该早期疾病阶段大脑中 Aβ 病理学的时间和相关性尚不清楚。在本研究中，我们旨在使用临床前 AD 的 App 基因敲入小鼠模型来研究这些关系。

方法

从 3 至 18 个月大的 App 基因敲入小鼠（n=48）和 2 至 18 个月大的 App 基因敲入小鼠（n=35）中收集 CSF、血清和脑组织。使用单分子阵列（Simoa）免疫测定法测量 CSF 和血清中 Aβ42 和 Aβ40 的浓度。通过免疫组织化学和硫黄素 S 染色评估脑组织切片中的大脑 Aβ 斑块负担。此外，使用电化学发光免疫测定法测量皮质组织匀浆中可溶性和不溶性部分中 Aβ42 的浓度。

结果

在 App 基因敲入小鼠中，CSF 和血清中的 Aβ42/Aβ40 比值分别从 12 个月和 16 个月龄开始显著降低。这些生物标志物的最初降低与大脑 Aβ 病理学同时发生，从大约 12 个月龄开始观察到更广泛的 Aβ 斑块负担和大脑中 Aβ42 水平升高。因此，在整个研究人群中，CSF 和血清中的 Aβ42/Aβ40 比值与大脑 Aβ 斑块负担以及大脑中可溶性和不溶性 Aβ42 的水平呈负双曲线关联。与血清相比，CSF 中的这些测量值的相关性更强。相比之下，在观察期间，App 基因敲入小鼠中未发现研究中的液体生物标志物或明显的大脑 Aβ 斑块病理学改变。

结论

我们的研究结果表明，在 App 基因敲入小鼠中存在一个时间序列事件，即大脑中 Aβ 聚集体的最初沉积后，一旦大脑 Aβ 病理学变得明显，CSF 和血清中的 Aβ42/Aβ40 比值就会下降。我们的结果还表明，与血清相比，当在 CSF 中评估时，所研究的生物标志物与大脑 Aβ 病理学的测量值相关性更强。