PMID:15122901

Citation	Qyang, Y, Chambers, SM, Wang, P, Xia, X, Chen, X, Goodell, MA and Zheng, H (2004) Myeloproliferative disease in mice with reduced presenilin gene dosage: effect of gamma-secretase blockage. Biochemistry 43:5352-9
Abstract	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.
Links	PubMed Online version:10.1021/bi049826u
Keywords	Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cell Lineage/genetics; Colony-Forming Units Assay; Endopeptidases/metabolism; Endopeptidases/physiology; Female; Gene Dosage; Granulocytes/pathology; Hematopoiesis/genetics; Leukocyte Count; Macrophages/pathology; Male; Membrane Proteins/deficiency; Membrane Proteins/genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloproliferative Disorders/enzymology; Myeloproliferative Disorders/genetics; Myeloproliferative Disorders/pathology; Presenilin-1; Presenilin-2; Protease Inhibitors/pharmacology
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