Statistical aspects of quantitative image analysis of beta-amyloid in the APP(V717F) transgenic mouse model of Alzheimer's disease.

Cerebral beta-amyloidosis is a central part of the neuropathology of Alzheimer's disease (AD). Quantitation of beta-amyloid plaques in the human AD brain, and in animal models of AD, is an important study endpoint in AD research. Methodologic approaches to the measurement of beta-amyloid in the brain vary between investigators, and these differences affect outcome measures. Here, one quantitative approach to the measurement of beta-amyloid plaques in brain sections was analyzed for sources of variability due to sampling. Brain tissue was from homozygous APP(V717F) transgenic male mice. Sampling variables were at the mouse and microscopic slide and field levels. Results indicated that phenotypic variability in the mouse sample population was the largest contributor to the standard error of the analyses. Within each mouse, variability between slides or between fields within slides had smaller effects on the error of the analyses. Therefore, when designing studies of adequate power, in this and in other similar models of cerebral beta-amyloidosis, sufficient numbers of mice per group must be included in order for change in mean plaque burden attributable to an experimental variable to outweigh phenotypic variability.

Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease.

We quantified the amount of amyloid beta-peptide (Abeta) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APP(V717F+/-) TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP(V717F+/-) Apoe(-/-) TG mice as old as 22 mo of age, whereas age-matched APP(V717F +/-) Apoe(+/-) and Apoe(+/+) TG mice display abundant amyloid deposition. The amount of Abeta immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe(+/+) > Apoe(+/-) >> Apoe(-/-)), and no Abeta immunoreactivity was detected in the cerebral cortex of APP(V717F+/-) Apoe(-/-) TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both Abeta(1-40) and Abeta(1-42) immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP(V717F) TG mice. ApoE immunoreactivity was detected in a subset of Abeta immunoreactive deposits and in virtually all thioflavine-S-fluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP(V717F) transgene nor its processing to Abeta peptide(s), we postulate that apoE promotes both the deposition and fibrillization of Abeta, ultimately affecting clearance of protease-resistant Abeta/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.

Tryptase inhibitors block allergen-induced airway and inflammatory responses in allergic sheep.

Tryptase, a mast cell serine protease, has been implicated in the pathophysiology of allergic asthma, but formal evidence to support this hypothesis has been limited by the lack of specific inhibitors for use in vivo. Therefore, in this study we examined the effects of two inhibitors of tryptase, APC 366 [N-(1-hydroxy-2-naphthoyl)-L-arginyl-L-prolinamide hydrochloride] and BABIM [bis(5-amidino-2-benzimidazolyl)methane] on antigen-induced early and late responses, airway responsiveness as measured by carbachol provocation, microvascular permeability as measured by bronchoalveolar lavage (BAL) albumin concentrations, and tissue eosinophilia from biopsies in allergic sheep. APC 366 and BABIM were administered by aerosol in all experiments. In vehicle control trials, antigen challenge resulted in peak early and late increases in specific lung resistance (SRL) of (mean +/- SE, n = 6) 259 +/- 30% and 183 +/- 27% over baseline, respectively. Treatment with APC 366 (9 mg/3 ml H2O given 0.5 h before, 4 h after, and 24 h after antigen challenge) slightly reduced the peak early response (194 +/- 41%), but significantly inhibited the late response (38 +/- 6%, p < 0.05 versus control trials). Twenty-four hours after challenge, APC 366 also completely blocked the antigen-induced airway hyperresponsiveness to inhaled carbachol observed in the control trial.(ABSTRACT TRUNCATED AT 250 WORDS)