Abstract
Although amyloid-β42 (Aβ42) has been used as one of the core biomarkers for Alzheimer’s disease (AD) diagnosis, the dynamic changes of its different forms in the brain, blood, and even intestines and its correlation with the progression of AD disease remain obscure. Herein, we screened Aβ42-specific preferred antibody pairs 1F12/1F12 and 1F12/2C6 to accurately detect Aβ42 types using sandwich ELISA, including total Aβ42, Aβ42 oligomers (Aβ42Os), and Aβ42 monomers (Aβ42Ms). The levels of Aβ42 species in the brain, blood, and intestines of different aged APP/PS1 mice were quantified to study their correlation with AD progression. Total Aβ42 levels in the blood were not correlated with AD progression, but Aβ42Ms level in the blood of 9-month-old APP/PS1 mice was significantly reduced, and Aβ42Os level in the brain was significantly elevated compared to 3-month-old APP/PS1, demonstrating that the levels of Aβ42Ms and Aβ42Os in the blood and brain were correlated with AD progression. Interestingly, in 9-month-old APP/PS1 mice, the level of Aβ42 in the intestine was higher than that in 3-month-old APP/PS1 mice, indicating that the increased level of Aβ42 in the gastrointestinal organs may also be related to the progression of AD. Meanwhile, changes in the gut microbiota composition of APP/PS1 mice with age were also observed. Therefore, the increase in Aβ derived from intestinal tissues and changes in microbiome composition can be used as a potential early diagnosis tool for AD, and further used as an indicator of drug intervention to reduce brain amyloid.
Highlights
Alzheimer’s disease (AD) is an age-related, irreversible form of dementia that affects nearly 50 million people worldwide (Collaborators, 2019)
BALB/c mice were immunized with human Aβ42 peptide preparations, and a pool of approximately 1,500 clones was generated via hybridoma technology
75 of these clones reacted with Aβ monomers and oligomers in ELISA (Supplementary Figure 1A)
Summary
Alzheimer’s disease (AD) is an age-related, irreversible form of dementia that affects nearly 50 million people worldwide (Collaborators, 2019). A defining pathological feature of AD is the presence of extracellular deposits of aggregated amyloid-β (Aβ) in the form of senile plaques in specific brain tissues and vascular walls (Murphy and LeVine, 2010), the main components of Amyloid-β42 Detection in APP/PS1 Mice which are the peptide isoforms Aβ40 and Aβ42, of which Aβ42 predominates in neuritic plaques of AD (Gu and Guo, 2013; Hong and Yaqub, 2019). A 4–4.5 kDa peptide containing 39–42 residues, is produced by sequential proteolytic cleavage of amyloid precursor protein (APP), which is expressed in brain cells and peripheral tissues (such as adrenal gland, kidney, heart, liver, spleen, muscles, and blood vessels). The brain accumulation of Aβ aggregates is affected by the levels of Aβ42 in the brain and peripheral tissues, but the contribution of peripheral Aβ toward the progression of AD is poorly understood. Aβ42 monomers (Aβ42Ms), mainly α-helical and random coil structures, aggregate to form various soluble oligomers
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