Abstract
Total tau (t-tau) and phosphorylated tau (p-tau) protein elevations in cerebrospinal fluid (CFS) are well-established hallmarks of Alzheimer’s disease (AD), while the associations of serum t-tau and p-tau levels with AD have been inconsistent across studies. To identify more accessible non-invasive AD biomarkers, we measured serum tau proteins and associations with cognitive function in age-matched controls (AMC, n = 26), mild cognitive impairment group (MCI, n = 30), and mild-AD group (n = 20) according to the Mini-mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Global Deterioration Scale (GDS) scores. Serum t-tau, but not p-tau, was significantly higher in the mild-AD group than AMC subjects (p < 0.05), and there were significant correlations of serum t-tau with MMSE and GDS scores. Receiver operating characteristic (ROC) analysis distinguished mild-AD from AMC subjects with moderate sensitivity and specificity (AUC = 0.675). We speculated that tau proteins in neuronal cell-derived exosomes (NEX) isolated from serum would be more strongly associated with brain tau levels and disease characteristics, as these exosomes can penetrate the blood-brain barrier. Indeed, ELISA and Western blotting indicated that both NEX t-tau and p-tau (S202) were significantly higher in the mild-AD group compared to AMC (p < 0.05) and MCI groups (p < 0.01). In contrast, serum amyloid β (Aβ1–42) was lower in the mild-AD group compared to MCI groups (p < 0.001). During the 4-year follow-up, NEX t-tau and p-tau (S202) levels were correlated with the changes in GDS and MMSE scores. In JNPL3 transgenic (Tg) mice expressing a human tau mutation, t-tau and p-tau expression levels in NEX increased with neuropathological progression, and NEX tau was correlated with tau in brain tissue exosomes (tEX), suggesting that tau proteins reach the circulation via exosomes. Taken together, our data suggest that serum tau proteins, especially NEX tau proteins, are useful biomarkers for monitoring AD progression.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, currently afflicting over 35.6 million individuals worldwide [1,2]
Characteristics of Neuronal Cell-Derived Exosomes (NEX) we evaluated the correlations between serum t-tau levels and neurocognitive test scores becaTuosdeeotenrlmyinseerwumheth-tearusewruasmstiagunipfircoatnetilnys horigighienratienftrhoemAnDeurgornoaulpcselalsccaonrddienngtetrothEeLcISirAcurlaetsiuolnts. viSaernuemurto-ntaaul-dcoenricveendtreaxtioosnoemxehsib(iNteEdXa),wweaekisnoelgaatetidveexcosrroemlaetsiofnrowmithseMruMmSEussicnogreth(re=E−x0o.Q19u, ipck= 0E.X11, prFeicgiuprieta1tiDo)nasnodluptioosnitaivcecocrodrirneglatoioPnewreizth-GGoDnzSaslecozr[e27(r] =w0it.h22m, pin=o0r.m06o, dFifigucarteioSn1sAa)nbduthneonceonrrieclhateidon (NwEitXh) CbyDRim-SmOuBnsoccohreem(irca=l 0m.1e3t,hpod=s 0(.F2i7g,uFrieguS2reA)S.1TDo).eTnhsuere wtheereidaelnstoitynoansidgnqiufiaclaintyt ocof rEreXlaatniodns NbEeXtw, weeenchsearruamctepri-ztaeudiclerovveelssiocrleps-btayuN(Sa2n0o2S)i/gt-htat,uWreastitoerannbdlontetiunrgo,caongdnittrivanestmesitssicoonreesle(cFtirgounre m1iEcr,FosacnodpyFi(gTuEreMS)1
HNEX p-tau (S202) above 11.85 pg/mL distinguished Mild-AD from AMC subjects with 46.67% sensitivity but 100% specificity (AUC = 0.73, p = 0.03, Figure 2I), and a human neural exosomes (hNEX) p-tau (S202)/t-tau of 0.39 distinguished Mild-AD from AMC subjects with 93.75% sensitivity and 43.75% specificity (AUC = 0.6113, p = 0.28, Figure 2J). These findings suggest that hNEX p-tau (S202)/t-tau ratio may serve as reliable biomarkers for Mild-AD
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, currently afflicting over 35.6 million individuals worldwide [1,2]. The disease is characterized behaviorally by progressive dementia and pathologically by local accumulations of amyloid β (Aβ) peptide and neurofibrillary tangles (NFTs) composed of tau protein in the brain [3]. Both Aβ accumulation and aggregation of tau in NFTs are believed to contribute directly to AD neurodegeneration and the associated cognitive deterioration [4]. In this study, we measured serum tau proteins, including tau proteins within the circulating EX fraction, in AD patients and age-matched controls at baseline and over disease progression to evaluate both the diagnostic efficacy of tau and the association with the severity of cognitive dysfunction. We measured EX tau in both the serum and brain tissue of JNPL3 mice expressing mutant human tau mutation (MAPT) to verify the EX-mediated transport of brain pathogenic proteins into the blood
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