Moderate reduction of gamma-secretase attenuates amyloid burden and limits mechanism-based liabilities.
Although gamma-secretase is recognized as a therapeutic target for Alzheimer's disease, side effects associated with strong inhibition of this aspartyl protease raised serious concerns regarding this therapeutic strategy. However, it is not known whether moderate inhibition of this enzyme will allow dissociation of beneficial effects in the CNS from mechanism-based toxicities in the periphery. We tested this possibility by using a series of mice with genetic reduction of gamma-secretase (levels ranging from 25 to 64% of control mice). Here, we document that even 30% reduction of gamma-secretase can effectively ameliorate amyloid burden in the CNS. However, global reduction of this enzyme below a threshold level increased the risk of developing squamous cell carcinoma as well as abnormal proliferation of granulocytes in a gamma-secretase dosage-dependent manner. Importantly, we demonstrate that there exists a critical gamma-secretase level that reduces the risk of amyloidosis in the CNS and limits tumorigenesis in epithelia. Our findings suggest that moderate inhibition of gamma-secretase represents an attractive anti-amyloid therapy for Alzheimer's disease.
Li
Tong
T
Department of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA. tli1@jhmi.edu
Wen
Hongjin
H
Brayton
Cory
C
Laird
Fiona M
FM
Ma
Guojun
G
Peng
Shiwen
S
Placanica
Lisa
L
Wu
T C
TC
Crain
Barbara J
BJ
Price
Donald L
DL
Eberhart
Charles G
CG
Wong
Philip C
PC
D000367:Age Factors; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D002490:Central Nervous System / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009154:Mutation / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics; D012878:Skin Neoplasms / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D053764:Presenilin-1; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases