Amyloid formation by the pro-inflammatory S100A8/A9 proteins in the ageing prostate.
BACKGROUND
The conversion of soluble peptides and proteins into polymeric amyloid structures is a hallmark of many age-related degenerative disorders, including Alzheimer's disease, type II diabetes and a variety of systemic amyloidoses. We report here that amyloid formation is linked to another major age-related phenomenon--prostate tissue remodelling in middle-aged and elderly men.


RESULTS
By using multidisciplinary analysis of corpora amylacea inclusions in prostate glands of patients diagnosed with prostate cancer we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. In prostate protease rich environment the amyloids are stabilized by dystrophic calcification and lateral thickening. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro under native and acidic conditions and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions.


CONCLUSIONS
These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate. The results provide strong support for the prediction that the generic ability of polypeptide chains to convert into amyloids could lead to their involvement in an increasing number of otherwise apparently unrelated diseases, particularly those associated with ageing.
Yanamandra
Kiran
K
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
Alexeyev
Oleg
O
Zamotin
Vladimir
V
Srivastava
Vaibhav
V
Shchukarev
Andrei
A
Brorsson
Ann-Christin
AC
Tartaglia
Gian Gaetano
GG
Vogl
Thomas
T
Kayed
Rakez
R
Wingsle
Gunnar
G
Olsson
Jan
J
Dobson
Christopher M
CM
Bergh
Anders
A
Elgh
Fredrik
F
Morozova-Roche
Ludmilla A
LA
D000368:Aged; D000375:Aging; D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism*; D002853:Chromatography, Liquid; D004275:DNA, Ribosomal / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D018625:Microscopy, Atomic Force; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D015032:Zinc / Q000378:metabolism
D000682:Amyloid; D040501:Calgranulin A; D040502:Calgranulin B; D004275:DNA, Ribosomal; D015032:Zinc; D002118:Calcium