Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice.
Presenilin (PS1) and (PS2) are the centers of gamma-secretase that release Abeta from APP in Alzheimer's disease (AD). They cleave signaling proteins like Notch and downregulate beta-catenin to modulate Wnt signaling. Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal 'Notch phenotype,' which has hampered investigation of PS function in adulthood seriously. We have thus turned towards PS1+/-PS2-/- mice which carry the most severe reduction of PS alleles compatible with survival, to analyze the consequences of impaired PS function especially in adulthood. In these 'partial deficient' mice, PS1 protein concentration is considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin downregulation. Their phenotype is normal up to approximately 6 months, when the majority of the mice develop an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis, as seen in human systemic lupus erythematosus. Besides B-cell dominated infiltrates, we observe a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies and an increased CD4+/CD8+ ratio. The mice further develop a benign skin hyperplasia similar to human seborrheic keratosis as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts. A partial reduction of PS function in PS1+/-PS2-/- mice causes a novel phenotype in adulthood unrelated to the developmental defects of full knockouts. As PS1+/-PS2+/- mice remain healthy, this points towards a sharply defined minimum of PS function. Skin and immune system appear to be especially sensitive targets of impaired PS function and may need careful monitoring if gamma-secretase inhibitors are envisaged for treating AD.
Tournoy
Jos
J
Neuronal Cell Biology Laboratory, Center for Human Genetics CB 4, University Hospital, Catholic University of Leuven, Belgium.
Bossuyt
Xavier
X
Snellinx
An
A
Regent
Marleen
M
Garmyn
Marian
M
Serneels
Lutgarde
L
Saftig
Paul
P
Craessaerts
Katleen
K
De Strooper
Bart
B
Hartmann
Dieter
D
D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D016282:Aspartic Acid Endopeptidases; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D017492:Keratosis, Seborrheic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D053764:Presenilin-1; D053766:Presenilin-2; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D051153:Wnt Proteins
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D000974:Antibodies, Antinuclear; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D051153:Wnt Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse