Myeloproliferative disease in mice with reduced presenilin gene dosage: effect of gamma-secretase blockage.
Mammalian presenilins (PS) consist of two highly homologous proteins, PS1 and PS2. Because of their indispensable activity in the gamma-secretase cleavage of amyloid precursor protein to generate Abeta peptides, inhibition of PS gamma-secretase activity is considered a potential therapy for Abeta blockage and Alzheimer's disease intervention. However, a variety of other substrates are also subject to PS-dependent processing, and it is thus imperative to understand the consequences of PS inactivation in vivo. Here we report a pivotal role of PS in hematopoiesis. Mice heterozygous for PS1 and homozygous for PS2 (PS1(+/)(-)PS2(-)(/)(-)) developed splenomegaly with severe granulocyte infiltration. This was preceded by an overrepresentation of granulocytic cells in the bone marrow and a greatly increased multipotent granulocyte-monocyte progenitor in the spleen. In contrast, hematopoietic stem cells and T- and B-lymphocytes were not affected. Importantly, treatment of wild-type splenocytes with a gamma-secretase inhibitor directly promoted the granulocyte-macrophage colony-forming unit (GM-CFU). These results establish a critical role of PS in myelopoiesis. Our finding that this activity can be directly modulated by its gamma-secretase activity has important safety implications concerning these inhibitors.
Qyang
Yibing
Y
Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.
Chambers
Stuart M
SM
Wang
Pei
P
Xia
Xuefeng
X
Chen
Xiaoli
X
Goodell
Margaret A
MA
Zheng
Hui
H
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019070:Cell Lineage / Q000235:genetics; D003114:Colony-Forming Units Assay; D010450:Endopeptidases / Q000378:metabolism* / Q000502:physiology; D005260:Female; D018628:Gene Dosage; D006098:Granulocytes / Q000473:pathology; D006410:Hematopoiesis / Q000235:genetics; D007958:Leukocyte Count; D008264:Macrophages / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors / Q000494:pharmacology*
D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse