Soluble cerebral Aβ protofibrils link Aβ plaque pathology to changes in CSF Aβ42/Aβ40 ratios, neurofilament light and tau in Alzheimer's disease model mice

被引：1

作者：

Andersson, Emelie ^{[1
]}

Lindblom, Nils ^{[1
,2
]}

Janelidze, Shorena ^{[1
]}

Salvado, Gemma ^{[1
]}

Gkanatsiou, Eleni ^{[3
]}

Soderberg, Linda ^{[3
]}

Moller, Christer ^{[3
]}

Lannfelt, Lars ^{[3
,4
]}

Ge, Junyue ^{[5
]}

Hanrieder, Joerg

Blennow, Kaj ^{[5
,6
]}

Deierborg, Tomas ^{[8
]}

Mattsson-Carlgren, Niklas ^{[1
,9
,10
]}

Zetterberg, Henrik ^{[5
,6
,7
,11
,12
,13
]}

Gouras, Gunnar ^{[2
]}

Hansson, Oskar ^{[1
,14
]}

机构：

[1] Lund Univ, Clin Memory Res Unit, Lund, Sweden

[2] Lund Univ, Dept Expt Med Sci, Expt Dement Res Unit, Lund, Sweden

[3] BioArct AB, Stockholm, Sweden

[4] Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden

[5] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden

[6] Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden

[7] UCL, Dept Neurodegenerat Dis, Queen Sq Inst Neurol, London, England

[8] Lund Univ, Dept Expt Med Sci, Expt Neuroinflammat Lab, Lund, Sweden

[9] Lund Univ, Skane Univ Hosp, Dept Neurol, Lund, Sweden

[10] Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden

[11] UCL, UK Dementia Res Inst, London, England

[12] Hong Kong Ctr Neurodegenerat Dis, Hong Kong, Peoples R China

[13] Univ Wisconsin, Wisconsin Alzheimers Dis Res Ctr, Sch Med & Publ Hlth, Madison, WI USA

[14] Skane Univ Hosp, Memory Clin, Malmo, Sweden

来源：

NATURE AGING | 2025年

基金：

欧洲研究理事会; 瑞典研究理事会;

关键词：

CEREBROSPINAL-FLUID; TRANSGENIC MICE; SENILE PLAQUES; MOUSE MODELS; BIOMARKERS; OLIGOMERS; BRAIN; NEURODEGENERATION; MUTATION; BLOOD;

D O I：

10.1038/s43587-025-00810-8

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The A beta 42/A beta 40 ratio in the cerebrospinal fluid (CSF) and the concentrations of neurofilament light (NfL) and total tau (t-tau) are changed in the early stages of Alzheimer's disease (AD)1, but their neurobiological correlates are not entirely understood. Here, we used 5xFAD transgenic mice to investigate the associations between these CSF biomarkers and measures of cerebral A beta, including A beta 42/A beta 40 ratios in plaques, insoluble fibrillar deposits and soluble protofibrils. A high A beta 42/A beta 40 ratio in soluble protofibrils was the strongest independent predictor of low CSF A beta 42/A beta 40 ratios and high CSF NfL and t-tau concentrations when compared to A beta 42/A beta 40 ratios in plaques and insoluble fibrillar deposits. Furthermore, the A beta 42/A beta 40 ratio in soluble protofibrils fully mediated the associations between the corresponding ratio in plaques and all the investigated CSF biomarkers. In AppNL-G-F/NL-G-F knock-in mice, protofibrils fully mediated the association between plaques and the CSF A beta 42/A beta 40 ratio. Together, the results suggest that the A beta 42/A beta 40 ratio in CSF might better reflect brain levels of soluble A beta protofibrils than insoluble A beta fibrils in plaques in AD. Furthermore, elevated concentrations of NfL and t-tau in CSF might be triggered by increased brain levels of soluble A beta protofibrils.

引用

页码：366 / 375

页数：22

共 48 条

[1] Hansson O., Biomarkers for neurodegenerative diseases, Nat. Med, 27, pp. 954-963, (2021)
[2] DeTure M.A., Dickson D.W., The neuropathological diagnosis of Alzheimeras disease, Mol. Neurodegener, 14, (2019)
[3] Hansson O., Lehmann S., Otto M., Zetterberg H., Lewczuk P., Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer’s Disease, Alzheimers Res. Ther, 11, (2019)
[4] Strozyk D., Blennow K., White L.R., Launer L.J., CSF Aβ 42 levels correlate with amyloid-neuropathology in a population-based autopsy study, Neurology, 60, pp. 652-656, (2003)
[5] Tapiola T., Et al., Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain, Arch. Neurol, 66, pp. 382-389, (2009)
[6] Janelidze S., Et al., CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer disease, Ann. Clin. Transl. Neurol, 3, pp. 154-165, (2016)
[7] Lewczuk P., Et al., Cerebrospinal fluid Aβ<sub>42/40</sub> corresponds better than Aβ<sub>42</sub> to amyloid PET in Alzheimer’s disease, J. Alzheimers Dis, 55, pp. 813-822, (2017)
[8] Mattsson-Carlgren N., Et al., Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease, Sci. Adv, 6, (2020)
[9] Blennow K., Zetterberg H., Biomarkers for Alzheimer’s disease: current status and prospects for the future, J. Intern. Med, 284, pp. 643-663, (2018)
[10] Iwatsubo T., Et al., Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43), Neuron, 13, pp. 45-53, (1994)

← 1 2 3 4 5 →