Modulation of [gamma]-Secretase Reduces [beta]-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease

• Published in: Neuron (Cambridge, Mass.) Vol. 67; no. 5; p. 769
• Main Authors: Kounnas, Maria Z, Danks, Anne M, Cheng, Soan, Tyree, Curtis, Ackerman, Elizabeth, Zhang, Xulun, Ahn, Kwangwook, Nguyen, Phuong, Comer, Dan, Mao, Long, Yu, Chengzhi, Pleynet, David, Digregorio, Paul J, Velicelebi, Gonul, Stauderman, Kenneth A, Comer, William T, Mobley, William C, Li, Yue-Ming, Sisodia, Sangram S, Tanzi, Rudolph E, Wagner, Steven L
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Limited 09.09.2010
• Subjects: Nonsteroidal anti-inflammatory drugs; Peptides; Rodents; Studies
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2010.08.018

Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Aβ42levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Aβ40levels while concomitantly elevating levels of Aβ38and Aβ37. Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain Aβ42; chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs).