Changes Of The Soluble TNFRs In Alzheimer's Disease And Its Underlying Mechanism

Alzheimer's disease (AD) is a progressive neurodegenerative disease, the clinical manifestation is deteriorating cognitive and memory function, decreased handling activity of daily living, and a variety of neuropsychiatric symptoms and behavioral disorders. To date, there are up to 29 million cases of AD patients all over the world, and this number is exponentially increasing. There are 500 million AD patients in China, and with an average of 30 million more patients each year. AD severely affects the health of the elderly, it has been ranked the fourth cause of death after cardiovascular disease, cerebrovascular disease and cancer in elderly patients. In AD brains, there are significant inflammatory responses and independent immune responses, especially around the senile plaques. There is a large number of activated microglias around the senile plaques, releasing lots of cytokines, complements, free radicals and other substances, eventually leading to cell dysfunction and death.Tumor necrosis factorα(TNFα) is one of the major inflammatory cytokines produced by activated astrocytes and microglia. There are two types of TNFαreceptors:the TNF receptor 1 (TNFR1) and receptor 2 (TNFR2). According to its existing forms, TNFRs can be divided into two categories:the receptor combined with the membrane of cell is called membrane TNFR (mTNFR); the other that is present in the serum and cerebrospinal fluid is called soluble TNFR (sTNFR). sTNFRs are formed from enzymatic digestion of the extracellular domain of mTNFRs, and released into the blood circulation modified by some enzymes. Therefore, the levels of sTNFRs could partially reflect the levels of mTNFRs. TNFR1 and TNFR2 are the substrates ofα-secretase TNFa enzyme (TACE). TACE not only participates in the production of sTNFRl and sTNFR2, but also is involved in the cleavage of TNFa, the amyloid precursor protein (APP) and other proteins. APP is the precursor protein ofβ-amyloid protein (Aβ). APP is first cleaved by theβ-site amyloid precursor protein cleavage enzyme 1 (BACE1) releasing a C99 peptide. C99 is then cleaved by y-secretase, releasing Ap. If the APP is cleaved by TACE before BACE1 cleavage, it will produce soluble APPα(sAPPα) fragment. This is because the TACE cleavage site is in the middle of Aβ. If APP is cleaved by TACE, it could significantly reduce the levels of brain Aβ.Previous studies showed activation of TNFR1, could result in the increased Aβlevels by increasing BACE1 levels and its enzymatic activity. The sTNFRs levels were found increased in the cerebrospinal fluid (CSF) and plasma in mild cognitive impairment patients. However, there are no reports relating to their changes in AD. In this study, using enzyme-linked immunosorbent assay (ELISA), enzyme activity assay and other experimental methods, we observed the sTNFR1 and sTNFR2 levels and TACE activity in CSF and plasma in AD patients. The results were as follows:1. There were higher levels of sTNFR1 in both CSF and plasma in AD, compared with age and sex-matched controls (P<0.05).2. In the subjects with AD, there were significantly higher levels of TNFR2, compared with age and sex-matched controls in both CSF and plasma (P<0.05).3. In AD patients there were higher levels of TACE enzymatic activity in both CSF and plasma when compared with age and sex-matched controls (P<0.05).4. Levels of sTNFR1 in CSF are positively correlated to the levels of sTNFR2 in AD patients and healthy controls (rsAD=0.663, rsHC=0.567, P<0.01, A) in the plasma in AD patients. There were significantly correlations between sTNR1 and sTNFR2 (rs=0.526, P<0.001, B), but there was no correlation between them in the plasma of healthy controls.5. Levels of both sTNFR in CSF are correlated positively to the levels of TACE activity in both AD patients and healthy controls (rs1AD= 0.541, rs2AD=0.508, rs1HC=0.491, rs2HC=0.557, P< 0.05, A); There were also significantly correlations between sTNFR1 and TACE activity (rs=0.385, P< 0.01, B) in the plasma of AD patients, but there was no correlation between sTNFR2 and TACE activity. There was no any correlation between them in plasma of healthy controls.This study gives the direct evidence that the levels of sTNFRs are increased in AD patients, resulting from the increased TACE enzymatic activity. This might partially provide some experimental evidences that TNFRs are involved in the pathogenesis of AD and could act as an indicator of hematologic testing in AD.