Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Aβ42 prompted by exogenous fibrillary or soluble Aβ25-35 in human cortical astrocytes and neurons-Therapeutic relevance to Alzheimer's disease

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Armato, Ubaldo¹  Chiarini, Anna¹  Chakravarthy, Balu²  Chioffi, Franco³  Pacchiana, Raffaella¹  Colarusso, Enzo³  Whitfield, James F.²  Dal Pra, Ilaria¹ 

[1] Univ Verona, Histol & Embryol Sect, Dept Life & Reprod Sci, Sch Med, I-37134 Verona, Italy

[2] Natl Res Council Canada, Ottawa, ON K1A 0N6, Canada

[3] St Chiara Hosp, Neurosurg Unit, I-38122 Trento, Italy

关键词: Amyloid-beta;    Human astrocyte;    Human neuron;    NPS 2143;    NPS R-568;    Calcium-sensing receptor;   

DOI  :  10.1016/j.bbadis.2013.04.020

来源: Elsevier

【 摘 要 】

The amyloid-beta (A beta) hypothesis posits that accumulating A beta peptides (A beta s) produced by neurons cause Alzheimer's disease (AD). However, the A beta s contribution by the more numerous astrocytes remains undetermined. Previously we showed that fibrillar (f)A beta(25-35), an A beta(42) proxy, evokes a surplus endogenous A beta(42) production/accumulation in cortical adult human astrocytes. Here, by using immunocytochemistry, immunoblotting, enzymatic assays, and highly sensitive sandwich ELISA kits, we investigated the effects of fA beta(25-35) and soluble (s)A beta(25-35) on A beta(42) and A beta(40) accumulation/secretion by human cortical astrocytes and HCN-1A neurons and, since the calcium-sensing receptor (CaSR) binds A beta s, their modulation by NPS 2143, a CaSR allosteric antagonist (calcilytic). The fA beta(25-35)-exposed astrocytes and surviving neurons produced, accumulated, and secreted increased amounts of A beta(42), while A beta(40) also accrued but its secretion was unchanged. Accordingly, secreted A beta(42)/A beta(40) ratio values rose for astrocytes and neurons. While slightly enhancing A beta(40) secretion by fA beta(25-35)-treated astrocytes, NPS 2143 specifically suppressed the fA beta(25-35)-elicited surges of endogenous A beta(42) secretion by astrocytes and neurons. Therefore, NPS 2143 addition always kept A beta(42)/A beta(40) values to baseline or lower levels. Mechanistically, NPS 2143 decreased total CaSR protein complement, transiently raised proteasomal chymotrypsin activity, and blocked excess NO production without affecting the ongoing increases in BACE1/beta-secretase and gamma-secretase activity in fA beta(25-35)-treated astrocytes. Compared to fA beta(25-35), sA beta(25-35) also stimulated A beta(42) secretion by astrocytes and neurons and NPS 2143 specifically and wholly suppressed this effect. Therefore, since NPS 2143 thwarts any A beta/CaSR-induced surplus secretion of endogenous A beta(42) and hence further vicious cycles of A beta self-induction/secretion/spreading, calcilytics might effectively prevent/stop the progression to full-blown AD. (C) 2013 Elsevier B.V. All rights reserved.

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