Alzheimer Disease: Shineman D

Fillit H, Nash DT, Shineman D. · Institute for the Study of Aging and Alzheimer's Drug Discovery Foundation, New York, NY, USA. · Alzheimers Dement. · Pubmed #19328448 No free full text.

This publication has no abstract.

Cheung KH, Shineman D, Müller M, Cárdenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK. · Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA. · Neuron. · Pubmed #18579078 links to  free full text

Abstract: Mutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD) and have been associated with calcium (Ca2+) signaling abnormalities. Here, we demonstrate that FAD mutant PS1 (M146L)and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP3. These interactions result in exaggerated cellular Ca2+ signaling in response to agonist stimulation as well as enhanced low-level Ca2+signaling in unstimulated cells. Parallel studies in InsP3R-expressing and -deficient cells revealed that enhanced Ca2+ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP3R stimulates amyloid beta processing,an important feature of AD pathology. These observations provide molecular insights into the "Ca2+ dysregulation" hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention.

Sung S, Yang H, Uryu K, Lee EB, Zhao L, Shineman D, Trojanowski JQ, Lee VM, Praticò D. · Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA. · Am J Pathol. · Pubmed #15579461 links to  free full text

Abstract: Epidemiological studies show that some nonsteroidal anti-inflammatory drugs, nonspecific inhibitors of the cyclooxygenase enzyme, reduce the incidence of Alzheimer's disease (AD). We determined the impact of two nonsteroidal anti-inflammatory drugs on A beta levels, deposition, and metabolism in a mouse model (the Tg2576) of AD-like amyloidosis. To this end, mice were treated with indomethacin and nimesulide continuously from 8 months of age until they were 15 months old. At the end of the study, indomethacin significantly reduced A beta(1-40) and A beta(1-42) levels in both cortex and hippocampus. This decrease was coincidental with a significant reduction of the nuclear factor (NF)-kappa B activity. By contrast, nimesulide had no effect on both A beta peptides and NF-kappa B. Consistently, mice receiving indomethacin, but no nimesulide, showed a significant reduction in the amyloid burden compared with placebo. Neither drug had an effect on plasma levels of A beta peptides or the A beta precursor protein metabolism. In vitro studies confirmed that genetic absence of this factor reduces the anti-amyloidogenic effect of indomethacin. These findings indicate that chronic administration of indomethacin by blocking the activation of the NF-kappa B significantly reduces the amyloid pathology in Tg2576 mice, and provide insights into the mechanisms by which this drug could slow progression of AD.