Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death.
Converging evidence suggests that the accumulation of cerebral amyloid beta-protein (Abeta) in Alzheimer's disease (AD) reflects an imbalance between the production and degradation of this self-aggregating peptide. Upregulation of proteases that degrade Abeta thus represents a novel therapeutic approach to lowering steady-state Abeta levels, but the consequences of sustained upregulation in vivo have not been studied. Here we show that transgenic overexpression of insulin-degrading enzyme (IDE) or neprilysin (NEP) in neurons significantly reduces brain Abeta levels, retards or completely prevents amyloid plaque formation and its associated cytopathology, and rescues the premature lethality present in amyloid precursor protein (APP) transgenic mice. Our findings demonstrate that chronic upregulation of Abeta-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo.
Leissring
Malcolm A
MA
Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Harvard Medical School, Boston, MA 02115, USA.
Farris
Wesley
W
Chang
Alice Y
AY
Walsh
Dominic M
DM
Wu
Xining
X
Sun
Xiaoyan
X
Frosch
Matthew P
MP
Selkoe
Dennis J
DJ
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D006801:Humans; D007339:Insulysin / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015260:Neprilysin / Q000096:biosynthesis / Q000235:genetics; D010447:Peptide Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D015996:Survival Rate; D015854:Up-Regulation / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010447:Peptide Hydrolases; D015260:Neprilysin; D007339:Insulysin