Nicotine is the principal psychoactive ingredient in cigarette smoke, and has been associated with health problems in humans. However, the pure form of nicotine may prove to be a valuable pharmaceutical agent for the treatment of AD. However, the beneficial effects of nicotine remain a matter of much controversy. In order to clarify this issue, 12-month-old transgenic mice, expressing neuron-specific enolase (NSE)-controlled APPsw, were treated with low, middle, and high doses of nicotine for 6 months. Herein, we have concluded that the nicotine-treated groups evidenced improvements in behavior and increases in the nicotine acetylcholine receptor, nAchRalpha7. These findings provide experimental evidence that nicotine effects an improvement in impaired memory, and that this improvement is associated with an increase in nAchRalpha7. Thus, nicotine may prove a good preventative or therapeutic modality for AD patients.

Insulin-degrading enzyme (IDE) is a 110-kDa thiol zinc-methalloendopeptidase that can cleave small Abeta peptides and the APP intracellular domain (AICD). The aim of this study was to examine aging-related correlation of IDE with gamma-secretase-generated products involving insulin and glucose levels in transgenic brains expressing neuron-specific enolase (NSE)-controlled human mutant presenilin-2 (hPS2m). Herein, we concluded that the levels of IDE expression in transgenic brains were decreased relative to those of control mice at 15 months of age. In parallel, inhibition in the IDE expression at this age underlies to the levels-up of Abeta-42, AICD, gamma-secretase, and glucose with a level-down of insulin. Thus, IDE expression is critical target for the therapeutic trials.

The complexity of Alzheimer's disease (AD) has made it difficult to examine its underlying mechanisms. A gene microarray offers a solution to the complexity through parallel analysis of most of the genes expressed in the hippocampal tissues from AD-transgenic and age-matched control littermates. This study examined the potential effect of APPsw over-expression on the modulation of genes for AD. To accomplish this, an oligonucleotide array was used with the large-scale screening of the hippocampus mRNA from 12-month-old APPsw-transgenic and control mice. There was a total of 116 differentially expressed genes, 59 up-regulated and 57 down-regulated, in the hippocampal region of the transgenic mice compared with the control mice. Initially, two of each of the down-regulated (Xlr3b and Mup3) and up-regulated genes (Serpina9 and Ccr6) were chosen for further investigation if the magnitude of change in these genes on the oligonucleotide array would correspond to those in the RT-PCR analysis from APPsw-transgenic mice. We also found that the changes in the differentially expressed genes are reliable. Thus, these genes might associate with AD neuropathology in neurodegenerative process of AD, although relevance of long lists altered genes should be evaluated in a future study.

PEN-2 is a component of the gamma-secretase complex, which is involved in the cleavage of the beta-amyloid precursor protein. The aim of this study was to determine the mechanism by which PEN-2 overexpression regulates gamma-secretase expression and the production of Abeta-42. In order to determine this, a hybrid gene harboring human PEN-2 was constructed, and used in the transfection of SK-N-MC human neuroepitheliomal cells. This cell line was also co-transfected with a combination of human mutant presenilin 2 (hPS2m) and APPsw. Our results indicated that (i) human PEN-2 overexpression induced an increase in gamma-secretase activity and its proteins, including PS1-CTF, APH-1, and nicastrin, thus production of Abeta-42, (ii) co-transfection of human PEN-2 with both hPS2m and APPsw exerted no more profound effects on the induction of gamma-secretase proteins and its activity than did transfection with hPEN-2 alone. Thus, PEN-2 overexpression may facilitate assembly into the more active gamma-secretase complex, and may also induce an increase in activity, thus affecting Abeta-42 production.