Alzheimer's disease (AD) is the most common form of dementia and is associated with the deposition of the 39- to 43-amino acid beta-amyloid peptide (Abeta) in the brain. C-terminal fragments (CTFs) of amyloid precursor protein (APP) can accumulate in endosomally derived multivesicular bodies (MVBs). These intracellular structures contain intraluminal vesicles that are released from the cell as exosomes when the MVB fuses with the plasma membrane. Here we have investigated the role of exosomes in the processing of APP and show that these vesicles contain APP-CTFs, as well as Abeta. In addition, inhibition of gamma-secretase results in a significant increase in the amount of alpha- and beta-secretase cleavage, further increasing the amount of APP-CTFs contained within these exosomes. We identify several key members of the secretase family of proteases (BACE, PS1, PS2, and ADAM10) to be localized in exosomes, suggesting they may be a previously unidentified site of APP cleavage. These results provide further evidence for a novel pathway in which APP fragments are released from cells and have implications for the analysis of APP processing and diagnostics for Alzheimer's disease.
The marsupial genus Antechinus is a group of small carnivorous marsupials from the order Dasyuromorphia (Family Dasyuridae) and is found in eastern Australia. The life history of all species in the genus is characterized by a complex, but highly synchronized life cycle in both sexes, culminating in a short mating period followed by total male mortality (semelparity). The breeding season is defined by a specific rate of increase in photoperiod, which is different for each species. In Antechinus spp., male mortality is due to the effects of high free testosterone and cortisol levels on many organ systems. Unusually, spermatogenesis is complete before testosterone levels begin to rise at the winter solstice. In males, low sperm counts have been compensated for by high proportions of sperm reaching the isthmus of the female reproductive tract and long-term storage in the crypts. The females survive to rear their young and may mate again in their second year. Gestation lasts from 26 to 34 days, depending on the species. However, developmental arrest can occur at several stages during embryogenesis, elongating the apparent gestation duration by several days. Several species have strong female sex biases in their litters. The high degree of life history synchrony and the cascade of endocrine-driven physiological events that result in male death are unusual physiological characteristics for mammals. Suggestions why semelparity may have evolved in Antechinus are discussed.
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