VEGF causes translocation of Syx from endothelial cell junctions, promoting junction disassembly, whereas Angtiopoietin-1 maintains Syx at the junctions and stabilizes them.

7-Ketocholesterol (7kchol) is prominent in atherosclerotic lesionswaf1 restored apoptosis. Stat1 and p21 waf1 were essential for downstream apoptotic events, including cytochrome c release from mitochondria and activation of caspases 9 and 3. Our data reveal key elements of the cellular pathway through which an important oxysterol induces apoptosis. Identification of the essential signaling events that may pertain in vivo could suggest targets for therapeutic intervention.

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Recent studies have suggested a possible role for presenilin proteins in apoptotic cell death observed in Alzheimer's disease. The mechanism by which presenilin proteins regulate apoptotic cell death is not well understood. Using the yeast two-hybrid system, we previously isolated a novel protein, presenilin-associated protein (PSAP) that specifically interacts with the C terminus of presenilin 1 (PS1), but not presenilin 2 (PS2). Here we report that PSAP is a mitochondrial resident protein sharing homology with mitochondrial carrier protein. PSAP was detected in a mitochondria-enriched fraction, and PSAP immunofluorescence was present in a punctate pattern that colocalized with a mitochondrial marker. More interestingly, overexpression of PSAP caused apoptotic death. PSAP-induced apoptosis was documented using multiple independent approaches, including membrane blebbing, chromosome condensation and fragmentation, DNA laddering, cleavage of the death substrate poly(ADP-ribose) polymerase, and flow cytometry. PSAP-induced cell death was accompanied by cytochrome c release from mitochondria and caspase-3 activation. Moreover, the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cell death, did not block the release of cytochrome c from mitochondria caused by overexpression of PSAP, indicating that PSAP-induced cytochrome c release was independent of caspase activity. The mitochondrial localization and proapoptotic activity of PSAP suggest that it is an important regulator of apoptosis.Alzheimer's disease (AD), 1 the most common form of senile dementia, is pathologically characterized by the deposition of amyloid ␤-peptide (A␤), the formation of neurofibrillary tangles, and massive neuronal cell loss in the brain (1).A subset of AD cases is familial AD (FAD), which occurs as an inherited autosomal dominant disease caused by defects in any of three genes: presenilin 1 (PS1) on chromosome 14, presenilin 2 (PS2) on chromosome 1, and the amyloid precursor protein (APP) on chromosome 21 (for review, see Ref.2). The majority of FAD cases have been associated with mutations in PS1 and PS2 (2). It has been shown that FAD-associated mutations in PS1 and PS2 affect the processing of APP, leading to an increased production of the more amyloidogenic A␤ peptide, both in vivo and in vitro (3-6). In addition to their roles in APP processing, roles for PS1 and PS2 in programmed cell death or apoptosis have also been reported in several studies. It has been shown that overexpression of a C-terminal fragment of PS2 protects neural cells against apoptosis (7). It was also reported that overexpression of a C-terminal fragment of PS1 delays anti-Fas-induced apoptosis in Jurkat cells (8). A role for PS1 and PS2 in apoptosis is also supported by studies demonstrating that overexpression of PS1 or PS2 bearing FAD mutations results in increased sensitivity to apoptotic insults (9 -13). These studies suggest that mutant PS1 and PS2 may be directly involved in neuronal cell death found in the AD brain...

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