Beta-secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice.
Alzheimer disease is intimately linked to an excess amount of amyloid-β (Aβ) in the brain. Thus, therapeutic inhibition of Aβ production is an attractive clinical approach to treat this disease. Here we provide the first direct experimental evidence that the treatment of Tg2576 transgenic mice with an inhibitor of β-secretase, GRL-8234, rescues the age-related cognitive decline. We demonstrated that the injected GRL-8234 effectively enters the brain and rapidly decreases soluble Aβ in the brain of Tg2576 mice. The rescue of cognition, which was observed only after long-term inhibitor treatment ranging from 5 to 7.5 mo, was associated with a decrease of brain amyloid-β plaque load. We also found no accumulation of amyloid-β precursor protein after several months of inhibitor treatment. These observations substantiate the idea that Aβ accumulation plays a major role in the cognitive decline of Tg2576 mice and support the concept of Aβ reduction therapy as a treatment of AD.
Protein Studies Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, USA.
Wan-Pin
WP
Chang
Xiangping
X
Huang
Deborah
D
Downs
John R
JR
Cirrito
Gerald
G
Koelsch
David M
DM
Holtzman
Arun K
AK
Ghosh
Jordan
J
Tang
D000375:Aging; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D004334:Drug Administration Schedule; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D010795:Phthalic Acids / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D016564:Amyloid beta-Protein Precursor; C556917:GRL 8234; D010795:Phthalic Acids; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases