AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss

Beta amyloid (Abeta), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimer's disease. Recent studies indicate that this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Abeta employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is necessary and sufficient to produce loss of dendritic spines and synaptic NMDA responses. Our studies indicate the central role played by AMPA receptor trafficking in Abeta-induced modification of synaptic structure and function.     

Size Dependent Sexual Selection in Drosophila ananassae

Mate choice based on body size is widespread and can have numerous consequences. We present data, which show the effect of male and female body size on sexual selection in Drosophila ananassae. The relationships between wing size, locomotor activity, mating latency, courtship pattern, fertility and mating success were studied. Mating latency was negatively correlated with wing length and with locomotor activity, while wing length and locomotor activity was positively correlated in males as well as in females. In female- and male-choice, we found that mate choice influenced size-assortative mating by: (1) large and small males preferring to mate with large females, (2) large males successfully competing for large females, leaving small males to mate with small females. Males increased their reproductive success by mating with large and more fecund females. In addition, in pairs of long/short winged flies, long winged flies courted and mated more successfully than short winged flies and they also have longer duration of copulation and more progeny than short winged flies. We found sterile mating in pairs of small winged males and females.     

Familial Alzheimer disease-linked presenilin 1 variants enhance production of both Abeta 1-40 and Abeta 1-42 peptides that are only partially sensitive to a potent aspartyl protease transition state inhibitor of "gamma-secretase"

Presenilin 1 (PS1) plays an essential role in intramembranous "gamma-secretase" processing of several type I membrane proteins, including the beta-amyloid precursor proteins (APP) and Notch1. In this report, we examine the activity of two familial Alzheimer's disease-linked PS1 variants on the production of secreted Abeta peptides and the effects of L-685,458, a potent gamma-secretase inhibitor, on inhibition of Abeta peptides from cells expressing these PS1 variants. We now report that PS1 variants enhance the production and secretion of both Abeta1-42 and Abeta1-40 peptides. More surprisingly, whereas the IC(50) for inhibition of Abeta1-40 peptide production from cells expressing wild-type PS1 is approximately 1.5 microm, cells expressing the PS1deltaE9 mutant PS1 exhibit an IC(50) of approximately 4 microm. Immunoprecipitation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry reveal that the levels of Abeta1-43 peptides are elevated in medium of PS1deltaE9 cells treated with higher concentrations of inhibitor. The differential effects of wild-type and mutant PS1 on gamma-secretase production of Abeta peptides and the disparity in sensitivity of these peptides to a potent gamma-secretase suggest that PS may be necessary, but not sufficient, to catalyze hydrolysis at the scissile bonds that generate the termini of Abeta1-40 and Abeta1-42 peptides.     

Effect of Temperature on Longevity and Productivity in Drosophila Ananassae: Evidence for Adaptive Plasticity and Trade-Off Between Longevity and Productivity

The genetic response of body size to temperature in the laboratory provides an interesting example of phenotypic plasticity. We found that females of Drosophila ananassae reared to adulthood at 18°C showed significant increase in body weight as compared to females reared at 25°C. At a given temperature, early productivity and lifetime productivity were the highest when the rearing and test temperature were the same. The effect of test temperature was highly significant for total productivity and early productivity. The interaction between test temperature and development temperature was also highly significant. Effect of development temperature was not significant. The females reared at 18°C showed greater body weight but their productivity was not significantly higher than smaller females reared at 25°C. Thus, the usually close relationship between size and fecundity is lost when the size change is due to rearing temperature. These findings provide evidence for adaptive plasticity in D. ananassae. We also found a negative correlation (trade-off) between longevity and productivity, the first report of such a trade-off between longevity and productivity in D. ananassae.     

Nebivolol: a selective beta(1)-adrenergic receptor antagonist that relaxes vascular smooth muscle by nitric oxide- and cyclic GMP-dependent mechanisms.

Nebivolol is a highly selective beta(1)-adrenergic receptor antagonist that also possesses vasodilator properties that are attributed largely to nitric oxide (NO). The objective of the present study was to elucidate in more detail the mechanisms by which nebivolol relaxes vascular smooth muscle. In the canine species, nebivolol caused relaxation of isolated precontracted rings of coronary artery and pulmonary artery largely by endothelium-dependent, NO-dependent, and cyclic GMP-dependent mechanisms. Vasorelaxation was inhibited by N(G)-methylarginine, and this inhibition was reversed by addition of excess L-arginine. Moreover, the vasorelaxant responses to nebivolol were markedly inhibited by oxyhemoglobin, methylene blue, and 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), whereas vasorelaxation was enhanced by zaprinast. Rat aortic ring preparations, however, relaxed in response to nebivolol by both endothelium-dependent and endothelium-independent mechanisms, both involving NO, and cyclic GMP. Endothelium-dependent and endothelium-independent vasorelaxation were inhibited by oxyhemoglobin, methylene blue, and ODQ. However, only endothelium-dependent vasorelaxation in response to nebivolol was inhibited by N(G)-methylarginine. Additional experiments ruled out other endothelium-independent vasorelaxant mechanisms. In conclusion, the vasodilator responses to nebivolol involve NO and cyclic GMP in both vascular endothelial and smooth muscle cells.     

Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer's disease

Amyloid precursor protein (APP) generates the beta-amyloid peptide, postulated to participate in the neurotoxicity of Alzheimer's disease. We report that APP and APLP bind to heme oxygenase (HO), an enzyme whose product, bilirubin, is antioxidant and neuroprotective. The binding of APP inhibits HO activity, and APP with mutations linked to the familial Alzheimer's disease (FAD) provides substantially greater inhibition of HO activity than wild-type APP. Cortical cultures from transgenic mice expressing Swedish mutant APP have greatly reduced bilirubin levels, establishing that mutant APP inhibits HO activity in vivo. Oxidative neurotoxicity is markedly greater in cerebral cortical cultures from APP Swedish mutant transgenic mice than wild-type cultures. These findings indicate that augmented neurotoxicity caused by APP-HO interactions may contribute to neuronal cell death in Alzheimer's disease.     

Multiple effects of aspartate mutant presenilin 1 on the processing and trafficking of amyloid precursor protein

PS1 deficiency and expression of PS1 with substitutions of two conserved transmembrane aspartate residues ("PS1 aspartate variants") leads to the reduction of Abeta peptide secretion and the accumulation of amyloid precursor protein (APP) C-terminal fragments. To define the nature of the "dominant negative" effect of the PS1 aspartate variants, we stably expressed PS1 harboring aspartate to alanine substitutions at codons 257 (D257A) or 385 (D385A), singly or in combination (D257A/D385A), in mouse neuroblastoma, N2a cells. Expression of the PS1 aspartate variants resulted in marked accumulation of intracellular and cell surface APP C-terminal fragments. While expression of the D385A PS1 variant reduced the levels of secreted Abeta peptides, we now show that neither the PS1 D257A nor D257A/D385A variants impair Abeta production. Surprisingly, the stability of both immature and mature forms of APP is dramatically elevated in cells expressing PS1 aspartate variants, commensurate with an increase in the cell surface levels of APP. These findings lead us to conclude that the stability and trafficking of APP can be profoundly modulated by coexpression of PS1 with mutations at aspartate 257 and aspartate 385.     

Neurofibrillary tangles and beta-amyloid deposits in Alzheimer's disease.

Alzheimer's disease is characterized by the presence of abundant neurofibrillary tangles and beta-amyloid deposits in neocortex, hippocampus and amygdala. The major protein components of tangles and plaques have recently been identified. These findings, briefly reviewed here, will allow researchers to design investigations that will lead to an understanding of the pathogenesis of the disease and to the development of new therapeutic approaches that may result in an effective treatment.