Soluble TNF receptors are associated with Aβ metabolism and conversion to dementia in subjects with mild cognitive impairment.
OBJECTIVE
There is evidence supporting that tumor necrosis factor receptor (TNFR)-signaling can induce production of beta-amyloid (Aβ) in the brain. Moreover, amyloid-induced toxicity has been shown to be dependent on TNFR-signaling. However, it is still unclear whether TNFRs are involved in the early stages of dementia.


METHODS
We analyzed soluble TNFR1 and TNFR2 levels in plasma and cerebrospinal fluid (CSF) at baseline in 137 patients with mild cognitive impairment (MCI) and 30 age-matched controls. The MCI patients were followed for 4-6 years with an incidence of Alzheimer's disease (AD) or vascular dementia (VaD) of 15% per year.


RESULTS
The patients with MCI who subsequently developed these forms of dementias had higher levels of sTNFR1 and sTNFR2 in both CSF and plasma already at baseline when compared to age-matched controls (p<0.05). In the CSF of MCI subjects and controls the levels of both sTNFR1 and sTNFR2 correlated strongly with β-site APP-cleaving enzyme 1 (BACE1) activity (r(s)=0.53-0.68, p<0.01) and Aβ 40 levels (r(s)=0.59-0.71, p<0.001). Similarly, both sTNFRs were associated with Aβ 40 (r(s)=0.39-0.46, p<0.05) in plasma. Finally, the levels of both sTNFRs correlated with the axonal damage marker tau in the CSF of MCI subjects and controls (r(s)=0.57-0.83, p<0.001).


CONCLUSIONS
TNFR-signaling might be involved in the early pathogenesis of AD and VaD, and could be associated with beta-amyloid metabolism.
Buchhave
Peder
P
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden; Neuropsychiatric Clinic, Malmö University Hospital, Sweden.
Zetterberg
Henrik
H
Blennow
Kaj
K
Minthon
Lennart
L
Janciauskiene
Sabina
S
Hansson
Oskar
O
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000378:metabolism*; D015140:Dementia, Vascular / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D012016:Reference Values; D012995:Solubility; D018709:Statistics, Nonparametric
D016229:Amyloid beta-Peptides; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II