Rockefeller University

About: Rockefeller University is a education organization based out in New York, New York, United States. It is known for research contribution in the topics: Population & Gene. The organization has 15867 authors who have published 32938 publications receiving 2940261 citations. The organization is also known as: Rockefeller University & Rockefeller Institute.

Intraneuronal Alzheimer Aβ42 Accumulates in Multivesicular Bodies and Is Associated with Synaptic Pathology

Abstract: A central question in Alzheimer's disease concerns the mechanism by which β-amyloid contributes to neuropathology, and in particular whether intracellular versus extracellular β-amyloid plays a critical role. Alzheimer transgenic mouse studies demonstrate brain dysfunction, as β-amyloid levels rise, months before the appearance of β-amyloid plaques. We have now used immunoelectron microscopy to determine the subcellular site of neuronal β-amyloid in normal and Alzheimer brains, and in brains from Alzheimer transgenic mice. We report that β-amyloid 42 localized predominantly to multivesicular bodies of neurons in normal mouse, rat, and human brain. In transgenic mice and human Alzheimer brain, intraneuronal β-amyloid 42 increased with aging and β-amyloid 42 accumulated in multivesicular bodies within presynaptic and especially postsynaptic compartments. This accumulation was associated with abnormal synaptic morphology, before β-amyloid plaque pathology, suggesting that intracellular accumulation of β-amyloid plays a crucial role in Alzheimer's disease.

Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells.

Abstract: Interleukin-12 (IL-12), a 70-kDa heterodimeric cytokine composed of covalently linked p35 and p40 chains, is to date the most critical factor for skewing the immune response towards a T helper 1 (Th1) of cytokine profile [high interferon-gamma (IFN-gamma), low IL-4]. Established sources of IL-12 are stimulated macrophages, neutrophils and B cells. As dendritic cells (DC) process antigen in the periphery and then migrate to lymphoid organs to sensitize T cells and induce cell mediated immunity, we reasoned that DC should constitute a critical source of IL-12. The criteria used to detect IL-12 in DC were the demonstration of p40 and p35 mRNA (semiquantitative polymerase chain reaction, northern blotting, and in situ hybridization) as well as IL-12 protein (p70 enzyme-linked immunosorbent assay, p70 antigen capture followed by IFN-gamma bioassay, free p40 chain radioimmunoassay or immunoprecipitation). We found that conventional stimuli such as Staphylococcus aureus induced production of IL-12 by murine as well as human DC in amounts comparable to spleen cells, peritoneal macrophages or peripheral mononuclear cells. DC exhibited, however, features that had not been seen with other antigen-presenting cells: they produced bioactive IL-12 upon antigen-specific interaction with T cells without any other stimuli; in an allogeneic mixed leukocyte reaction model, neutralizing anti-IL-12 antibodies showed that DC-derived IL-12 was critical for optimal proliferation and IFN-gamma production by activated Th1 blasts; and finally, the priming of resting, naive allogeneic T cells by DC, followed by restimulation of primed T blasts by DC, skewed the response to Th1 without the need for any exogenous cytokines or stimuli such as microorganisms. This skewing to Th1 cytokine production, which depended on DC-derived IL-12, but did not require anti-IL-4, exogenous IL-12, or microbes, might be a major function of DC.

Signal recognition particle contains a 7S RNA essential for protein translocation across the endoplasmic reticulum.

Abstract: In addition to its previously characterized, six different polypeptide components, signal recognition protein--which functions in protein translocation across and integration into the endoplasmic reticulum membrane--contains a 7S RNA molecule. The RNA is closely identified with the small cytoplasmic 7SL RNA and is required for both structural and functional properties of signal recognition protein--which we therefore rename signal recognition particle.