The neuronal ubiquitin/proteasomal pathway has been implicated in the pathogenesis of Alzheimer's disease (AD). We now show that a component of the pathway, ubiquitin C-terminal hydrolase L1 (Uch-L1), is required for normal synaptic and cognitive function. Transduction of Uch-L1 protein fused to the transduction domain of HIV-transactivator protein (TAT) restores normal enzymatic activity and synaptic function both in hippocampal slices treated with oligomeric Abeta and in the APP/PS1 mouse model of AD. Moreover, intraperitoneal injections with the fusion protein improve the retention of contextual learning in APP/PS1 mice over time. The beneficial effect of the Uch-L1 fusion protein is associated with restoration of normal levels of the PKA-regulatory subunit IIalpha, PKA activity, and CREB phosphorylation.

Long-term feeding of adenine to rats produced metabolic abnormalities resembling chronic renal failure in humans. Among the disturbances produced were azotemia, accumulation of uremic toxins, metabolic imbalances of amino acids and electrolytes, and hormonal imbalances. The pathological findings in the kidneys of these experimental rats revealed lesions of proximal tubules, of some distal tubules and of glomeruli. Contracted kidneys were found in the rats with severe perturbations. Our results suggest that long-term adenine feeding provides a model which would be useful to study chronic renal failure.

The following two theories for the mechanism of ABCA1 in lipid efflux to apolipoprotein acceptors have been proposed: 1) that ABCA1 directly binds the apolipoprotein ligand and then facilitates lipid efflux and 2) that ABCA1 acts as a phosphatidylserine (PS) translocase, increasing PS levels in the plasma membrane exofacial leaflet, and that this is sufficient to facilitate apolipoprotein binding and lipid assembly. Upon induction of ABCA1 in RAW264.7 cells by cAMP analogues there was a moderate increase in cell surface PS as detected by annexin V binding, whereas apoAI binding was increased more robustly. Apoptosis induced large increases in annexin V and apoAI binding; however, apoptotic cells did not efflux lipids to apoAI. Annexin V did not act as a cholesterol acceptor, and it did not compete for the cholesterol acceptor or cell binding activity of apoAI. ApoAI binds to ABCA1-expressing cells, and with incubation at 37°C apoAI is co-localized within the cells in ABCA1-containing endosomes. Fluorescent recovery after photobleaching demonstrated that apoAI bound to ABCA1-expressing cells was relatively immobile, suggesting that it was bound either directly or indirectly to an integral membrane protein. Although ABCA1 induction was associated with a small increase in cell surface PS, these results argue against the notion that this cell surface PS is sufficient to mediate cellular apoAI binding and lipid efflux.The ATP binding cassette (ABC) 1 family of proteins serves to pump a diverse set of molecules out of cells. ABCA1, the Tangier disease gene, is required for cholesterol and phospholipid efflux to lipid-free apolipoproteins (for review see Ref. 1). The exact mechanism of this lipid efflux pump and the location of the lipid transfer and assembly onto apolipoprotein acceptors have yet to be determined definitively. It has been shown previously that ABCA1 expression leads to increased cell surface binding and uptake of apoAI (2). Protein cross-linking studies have shown that cell surface ABCA1 is closely associated with exogenously added apoAI (3, 4). Thus, one theory of ABCA1 action is that the apolipoprotein ligand is bound directly to the ABCA1 receptor, which can then mediate lipid assembly to form a nascent lipoprotein. An alternative theory of ABCA1 function has been put forth by Chimini and coworkers (5, 6). Phosphatidylserine (PS) is normally asymmetrically distributed on the plasma membrane such that most of it is sequestered on the inner leaflet. Increased levels of PS in the exofacial leaflet have been demonstrated in ABCA1 transiently transfected cells, thus providing evidence that ABCA1 may function as a PS translocase to pump PS from the cytoplasmic leaflet to the exofacial leaflet (5).This activity is referred to as "floppase" activity to distinguish it from the "flippase" activity that pumps PS from the outer to inner plasma membrane leaflets (7). These authors propose that PS translocase activity is sufficient to lead to apoAI binding to and lipid efflux from ABCA1-expressing cells and that...

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