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Based on aptamer technology and RPA reaction, we developed a new micro protein detection method —captamer . It can detect protein as low as 1pg / μL, and the reaction is very rapid, with only 20 minutes needed. We used it to detect very small amounts of tau protein in blood, which is an important biological index of Alzheimer's disease. It can be used for the early diagnosis of Alzheimer's disease and make it possible to explore the dynamic changes of blood markers of Alzheimer's disease with age, so as to lay a foundation for the elucidation of the disease mechanism.
Alzheimer's disease (AD) is a progressive neurodegenerative disease. The clinical manifestations of dementia are characterized by memory loss, aphasia, apraxia, agnosia, executive dysfunction, personality and behavior changes.
Fig1:AD prevalence with age and gender
Most of the patients are 50 years old and over, and the prevalence increases with age.
Fig2: Global distribution of AD
It is estimated that there were about 50 million patients with Alzheimer's disease worldwide in 2018, which is similar to the population of Kenya, Colombia or South Korea.
Fig3: Statistics and prediction of AD patients
According to ADI images(namely Alzheimer’s Disease International), the number of patients with Alzheimer's disease is increasing year by year and is expected to continue to increase in the future. The number of AD patients will reach an amazing 150 million in 2050.
At present, the annual cost of this disease is about $1 trillion, and it is estimated that the cost will double by 2030. The outcome of AD is irreversible damage to brain cells, which brings a great burden to patients and their families. It has become a serious global medical problem. Without effective therapy at present, once AD is diagnosed, it can’t be cured anymore. All these mentioned above inspired us to endeavor to find a convenient way for diagnosing AD in the early stage.
At present, the diagnosis methods of ad mainly include scale testing, gene detection and image assisted testing. Medical history analysis can be carried out according to medical and family history, and the patient can be preliminarily judged as early-onset or late-onset venereal disease. Neurological examination can be divided into neuropsychological evaluation, which can be carried out through various scales and experiments, and imaging examination includes structural magnetic resonance imaging. Therefore, we turn our attention to biomarker detection. Perhaps by detecting specific proteins, we can give warnings to AD patients early.
Although the Alzheimer disease isn’t completely understood, two major players that are often cited in its progression are plaques and tangles. β- Amyloid plaques can block the signal transmission between neurons, damage the memory function of the brain, activate the inflammatory response and further damage the surrounding neurons. tau protein can maintain the stability of microtubules in neuronal cells. People think that after the formation of β-amyloid plaque, it will promote protein kinase to phosphorylate tau protein and change its structure. Allosteric tau proteins can no longer maintain the stability of microtubules, but aggregate with other tau proteins. This forms another sign of AD, neurofibrillary tangles. Neurons with tangles and non-functioning microtubules can’t signal as well, and sometimes end up undergoing apoptosis, or programmed cell death. When neurons die, the brain shrinks. Some researches show that the content of tau protein in AD patients is significantly higher than that in normal people, so we chose tau protein as our research object.
Fig4: Measurement of tau protein in normal and patient blood by electrochemical sensor
Fig5: The content of tau protein was measured by immunological methods
Table1: Detection method of blood markers in AD
To date, AD biomarker-based expression techniques include mass spectrometry (MS), magnetic resonance imaging (MRI), enzyme linked immunosorbent assay (ELISA), Western-blot, immunohistochemistry, flexible Multi-Analyte Profiling (xMAP) and position emission tomography (PET).
As you can see, most methods have various application limitations. Even ELISA, the most practical method, can not be widely used because of its high cost and cumbersome operation.
Therefore, it is urgent to develop a new detection method, which can detect trace protein, with the characteristics of low cost and fast response.
We intend to develop a micro protein detection method based on nucleic acid aptamer to realize signal amplification through RPA reaction. When there is no protein, there is no or low signal. When there is protein, it can quickly generate monotonous fluorescent signals related to protein concentration. Further, we plan to develop a hardware for automatic sampling and real-time fluorescence detection, and a software for data storage and analysis. We call this technique captamer.
1. E. Nichols et al., Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology 18, 88-106 (2019).
2. S. Lisi et al., Non-SELEX isolation of DNA aptamers for the homogeneous-phase fluorescence anisotropy sensing of tau Proteins. Anal Chim Acta 1038, 173-181 (2018).
3. N. J. Ashton et al., Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology. Acta Neuropathol 141, 709-724 (2021).
4. D. Tao et al., Development of a Label-Free Electrochemical Aptasensor for the Detection of Tau381 and its Preliminary Application in AD and Non-AD Patients' Sera. Biosensors (Basel) 9, (2019).
5. B. Shui et al., Biosensors for Alzheimer's disease biomarker detection: A review. Biochimie 147, 13-24 (2018).