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Residues 16 -20 of the ␤-amyloid peptide (A␤) function as a self-recognition element during A␤ assembly into fibers. Peptides containing this motif retain the ability to interact with A␤ and, in some cases, potently inhibit its assembly. Replacing L-with D-amino acids could stabilize such peptides and permit their evaluation as therapeutic agents for Alzheimer's disease. Here we have assessed the effect that such a chiral reversal has on inhibitory potency. D-enantiomers of five peptides, KLVFFA, KKLVFFA, KFVFFA, KIVFFA, and KVVFFA, were unexpectedly more active as inhibitors in an in vitro fibrillogenesis assay. Circular dichroism showed that D-KLVFFA more effectively prevented A␤ adopting the ␤-sheet secondary structure correlated with fibrillogenesis. Electron microscopy showed that fiber formation was also more strongly inhibited by D-KLVFFA. Heterochiral inhibition was confirmed using D-A␤, on the principle that enantiomeric proteins exhibit reciprocal chiral biochemical interactions. With D-A␤, L-KLVFFA was the more potent inhibitor, rather than D-KLVFFA. Most significantly, D-peptides were more potent at reducing the toxicity of both A␤ 1-40 and A␤ 1-42 toward neuronal cells in culture. This unforeseen heterochiral stereoselectivity of A␤ for D-peptide inhibitors should be considered during future design of peptide-based inhibitors of A␤ neurotoxicity and fibrillogenesis. ␤-Amyloid peptide (A␤)1 is a 4-kDa peptide that when assembled into amyloid, progressively accumulates in Alzheimer's disease (AD) (1, 2). The neurotoxic properties specifically associated with aggregated forms of this peptide provide key causal evidence linking A␤ to the pathology of AD (3, 4). This link is supported by A␤ immunization experiments in transgenic mice expressing mutant alleles of human amyloid precursor protein. Such vaccination reduces both the A␤ peptide levels and deposits in the brain (5) and also attenuates the associated cognitive impairment in these mice (6, 7). Subsequent studies showed that full assembly of A␤ into mature fibers similar to those found in plaques is not necessary for toxicity. Smaller aggregates with molecular weights corresponding to dimers (8, 9), trimers, and tetramers (10) exhibit toxicity in cell culture as well. These findings support and highlight the necessity that A␤ assembly intermediates be included as targets in AD drug development.While the delineation of which assembly intermediate(s) retain toxicity will aid in the rational design of specific inhibitors, screening assays have already identified a number of antifibrillogenic compounds (11-13). Studies show that the A␤ 16 -20 region is important for A␤ assembly (14, 15), possibly as an A␤ self-recognition motif (16). These findings led to the development of a series of peptides incorporating this sequence, which bind to the homologous region of A␤ and block its oligomerization (17). In another study an eleven residue peptide containing three prolines, which have a low propensity to form ␤-sheets, inhibited A␤ fibril formation (18). Pe...

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Captive American kestrels (Falco sparverius) were used to model the effect of low prey availability on growth and survivorship potential in nestling raptors. The experimental design consisted of 4 treatments: nestlings were fed ad libitum (100% diet) or on increasingly restricted diets (90, 80, and 70% of the ad libitum diet). Nestlings fed a reduced diet grew significantly more slowly than those fed the ad libitum diet, as shown by the body mass growth constant. The restricted diet had no significant effect on the asymptotic size of the kestrels, i.e., body mass and tarsus and antebrachium lengths. However, young kestrels fed reduced diets (80 and 70%) had a lower body mass at fledging than those fed ad libitum and the 90% diet, although they fledged at the same age. The growth of the ninth primary was slower for birds on restricted diets than for those fed ad libitum. Sexual dimorphism was observed for body mass and antebrachium growth constants, with males growing faster than females. However, females reached a higher asymptotic body mass and antebrachium length, as well as a higher body mass at fledging, than males. Thus, when prey availability is reduced by as much as 30%, nestling kestrels grow more slowly and store less fat, which could lead to poorer postfledging survivability.

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