Honey bees are social insects that exhibit striking caste-specific differences in longevity. Queen honey bees live on average 1-2 years whereas workers live 2 to 6 weeks in the summer and about 20 weeks in the winter. It is not clear whether queen-worker differences in longevity are due to intrinsic physiological differences in the rate of senescence, to differential exposure to extrinsic factors such as predation and adverse environmental conditions, or both. To determine if the relatively short life span of worker bees involves senescence, we measured age-specific resistance to three different physiological stressors (starvation, thermal, and oxidative stress) while eliminating agerelated differences in foraging activity and minimizing age-related differences in energy expenditure. Despite these manipulations, older worker bees were still significantly less resistant to all three stressors than were younger bees. These results indicate that the regulation of worker bee lifespan involves senescence, in addition to extrinsic factors.

Accumulation of the amyloid-beta (Aβ) peptide is a central factor in Alzheimer’s disease (AD) pathogenesis as supported by continuing evidence. This review concisely summarizes this evidence supporting a critical role for Aβ in AD before discussing the clearance of this peptide. Mechanisms of clearance of Aβ are critical for preventing pathological elevations in Aβ concentration. Direct degradation of Aβ by endopeptidases has emerged as one important pathway for clearance. Of particular interest are endopeptidases that are sensitive to the neprilysin (NEP) inhibitors thiorphan and phosphoramidon (i.e., are “NEP-like”) as these inhibitors induce a dramatic increase in Aβ levels in rodents. This review will focus on neprilysin-2 (NEP2), a NEP-like endopeptidase which cooperates with NEP to control Aβ levels in the brain. The evidence for the involvement of NEP2 in AD is discussed as well as the therapeutic relevance with regards to gene therapy and the development of molecular markers for the disease.

Proteases that degrade the amyloid-␤ peptide (A␤) are important in protecting against Alzheimer's disease (AD), and understanding these proteases is critical to understanding AD pathology. Endopeptidases sensitive to inhibition by thiorphan and phosphoramidon are especially important, because these inhibitors induce dramatic A␤ accumulation (ϳ30-to 50-fold) and pathological deposition in rodents. The A␤-degrading enzyme neprilysin (NEP) is the best known target of these inhibitors. However, genetic ablation of NEP results in only modest increases (ϳ1.5-to 2-fold) in A␤, indicating that other thiorphan/phosphoramidon-sensitive endopeptidases are at work. Of particular interest is the NEP homolog neprilysin 2 (NEP2), which is thiorphan/ phosphoramidon-sensitive and degrades A␤. We investigated the role of NEP2 in A␤ degradation in vivo through the use of gene knockout and transgenic mice. Mice deficient for the NEP2 gene showed significant elevations in total A␤ species in the hippocampus and brainstem/diencephalon (ϳ1.5-fold). Increases in A␤ accumulation were more dramatic in NEP2 knockout mice crossbred with APP transgenic mice. In NEP/NEP2 double-knockout mice, A␤ levels were marginally increased (ϳ1.5-to 2-fold), compared with NEP Alzheimer's disease (AD) is a neurodegenerative disorder currently affecting more than 26 million people worldwide and, as advances in modern medicine prolong lifespan, this number is expected to quadruple by 2050. 1 A major factor believed to be involved in the progression of AD pathology is the accumulation of amyloid-␤ peptide (A␤). Studying the mechanisms of A␤ clearance is, therefore, very important to understanding AD.Currently, enzymatic degradation is thought to play an integral role in the removal of A␤. Of the A␤-degrading enzymes, neprilysin (NEP) has been shown to be highly critical for cerebral A␤ control.2 NEP expression has also been inversely correlated with amyloid pathology in humans and mice, and NEP gene transfer has been reported to reduce amyloid pathology in transgenic mice (reviewed by Marr and Spencer 3 ). Despite the importance of NEP-mediated A␤ degradation, NEP knockout (KO) mice show only moderately elevated A␤ levels (1.5-to 2-fold), insufficient to cause plaque deposition. 4 However, when treated with thiorphan, an NEP endopeptidase inhibitor, mice and rats demonstrate pathological accumulations of A␤ after only 1 month. 2,5 This was also found in mice treated with phosphoramidon, another NEP inhibitor. 6 These results indicate that there may exist additional NEPlike endopeptidases in the metalloprotease 13 (M13) family that are central to the A␤ clearance pathway.The NEP homolog neprilysin 2 (NEP2) is one such endopeptidase. NEP2 (also known as MMEL1/2, SEP, NL1, NE-PLP) possesses a 55% sequence identity to NEP and has been shown to degrade vasoactive peptides. 7,8 In addition, the membrane-bound ␣-splice form of murine NEP2 has demonstrated A␤-degrading properties in membrane fractions. 9 In transduced HEK293T cells, our research group previously sho...

Alzheimer’s disease (AD) is the most prevalent form of dementia affecting the elderly. Evidence has emerged signifying that stimulation of the reelin pathway should promote neural plasticity and suppresses molecular changes associated with AD, suggesting a potential therapeutic application to the disease. This was explored through the use of lentiviral vector mediated overexpression of the reelin homolog, F-spondin, which is an activator of the reelin pathway. Intrahippocampal gene transfer of F-spondin improved spatial learning/memory in the Morris Water Maze and increased exploration of the novel object in the Novel Object Recognition test in wild-type mice. F-spondin overexpression also suppressed endogenous levels of amyloid beta (Aβ42) in these mice and reduced Aβ plaque deposition and improved synaptophysin expression in transgenic mouse models of AD. These data demonstrate pathologic and cognitive improvements in mice through F-spondin overexpression.