Oxysterol-Binding Protein-1 (OSBP1) Modulates Processing and Trafficking of the Amyloid Precursor Protein

BACKGROUND Evidence from biochemical, epidemiological and genetic findings indicates that cholesterol levels are linked to amyloid-β (Aβ) production and Alzheimer's disease (AD). Oxysterols, which are cholesterol-derived ligands of the liver X receptors (LXRs) and oxysterol binding proteins, strongly regulate the processing of amyloid precursor protein (APP). Although LXRs have been studied extensively, little is known about the biology of oxysterol binding proteins. Oxysterol-binding protein 1 (OSBP1) is a member of a family of sterol-binding proteins with roles in lipid metabolism, regulation of secretory vesicle generation and signal transduction, and it is thought that these proteins may act as sterol sensors to control a variety of sterol-dependent cellular processes. RESULTS We investigated whether OSBP1 was involved in regulating APP processing and found that overexpression of OSBP1 downregulated the amyloidogenic processing of APP, while OSBP1 knockdown had the opposite effect. In addition, we found that OSBP1 altered the trafficking of APP-Notch2 dimers by causing their accumulation in the Golgi, an effect that could be reversed by treating cells with OSBP1 ligand, 25-hydroxycholesterol. CONCLUSION These results suggest that OSBP1 could play a role in linking cholesterol metabolism with intracellular APP trafficking and Aβ production, and more importantly indicate that OSBP1 could provide an alternative target for Aβ-directed therapeutic.National Institute on Aging (AG/NS17485

A study of long-term potentiation in transgenic mice over-expressing mutant forms of both amyloid precursor protein and presenilin-1

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Synaptic transmission and long-term potentiation (LTP) in the CA1 region of hippocampal slices have been studied during ageing of a double transgenic mouse strain relevant to early-onset familial Alzheimer's disease (AD). This strain, which over-expresses both the 695 amino acid isoform of human amyloid precursor protein (APP) with K670N and M671L mutations and presenilin 1 with the A246E mutation, has accelerated amyloidosis and plaque formation. There was a decrease in synaptic transmission in both wildtype and transgenic mice between 2 and 9 months of age. However, preparing slices from 14 month old animals in kynurenic acid (1 mM) counteracted this age-related deficit. Basal transmission and paired-pulse facilitation was similar between the two groups at all ages (2, 6, 9 and 14 months) tested. Similarly, at all ages LTP, induced either by theta burst stimulation or by multiple tetani, was normal. These data show that a prolonged, substantially elevated level of Aβ are not sufficient to cause deficits in the induction or expression of LTP in the CA1 hippocampal region.Published versio

Neurotransmission in neonatal rat cardiac ganglion in situ

The intrinsic cardiac ganglia of the neonatal heart in situ were studied using electrophysiological and histochemical techniques. The vagal branches innervating the atrial myocardium and cardiac ganglia were identified and individual ganglion cells visualized using Hoffman modulation contrast optics. Histochemical studies revealed the presence of acetylcholinesterase activity associated with neuronal cell bodies and fibers, catecholamine-containing, small intensely fluorescent cells, and cell bodies and nerve fibers immunoreactive for vasoactive intestinal polypeptide. Intracellular recordings from the \u27principal\u27 cells of the rat cardiac ganglion in situ revealed a fast excitatory postsynaptic potential (EPSP) evoked after electrical stimulation of the vagus nerve, which was inhibited by the nicotinic receptor antagonist, mecamylamine. No spontaneously firing neurons were found, although infrequent (\u3c 2 min-1) spontaneous miniature EPSPs were observed in most neurons. The quantal content of neurally evoked responses was between 10 and 30 quanta, and the presence of multiple EPSPs in some cells suggested polyneuronal innervation. The neurally evoked EPSP amplitude was dependent on the rate of nerve stimulation, decreasing with increasing frequency of stimulation. Neurons exhibited a sustained depolarization during high frequency stimulation (\u3e 1 Hz), and in ~ 15% of the cells a slow depolarization lasting 1-3 min was observed after a train of stimuli. The presence of catecholamine- and neuropeptide-containing neuronal cell body fibers in neonatal rat cardiac ganglia in situ, along with neurally evoked postsynaptic responses resistant to cholinergic ganglionic blockers, suggests a role for noncholinergic transmission in the regulation of the mammalian heart beat

The association of clinical phenotypes to known AD/FTD genetic risk loci and their inter-relationship.

To elucidate how variants in genetic risk loci previously implicated in Alzheimer's Disease (AD) and/or frontotemporal dementia (FTD) contribute to expression of disease phenotypes, a phenome-wide association study was performed in two waves. In the first wave, we explored clinical traits associated with thirteen genetic variants previously reported to be linked to disease risk using both the 23andMe and UKB cohorts. We tested 30 additional AD variants in UKB cohort only in the second wave. APOE variants defining ε2/ε3/ε4 alleles and rs646776 were identified to be significantly associated with metabolic/cardiovascular and longevity traits. APOE variants were also significantly associated with neurological traits. ABI3 variant rs28394864 was significantly associated with cardiovascular (e.g. (hypertension, ischemic heart disease, coronary atherosclerosis, angina) and immune-related trait asthma. Both APOE variants and CLU variant were significantly associated with nearsightedness. HLA- DRB1 variant was associated with diseases with immune-related traits. Additionally, variants from 10+ AD genes (BZRAP1-AS1, ADAMTS4, ADAM10, APH1B, SCIMP, ABI3, SPPL2A, ZNF232, GRN, CD2AP, and CD33) were associated with hematological measurements such as white blood cell (leukocyte) count, monocyte count, neutrophill count, platelet count, and/or mean platelet (thrombocyte) volume (an autoimmune disease biomarker). Many of these genes are expressed specifically in microglia. The associations of ABI3 variant with cardiovascular and immune-related traits are one of the novel findings from this study. Taken together, it is evidenced that at least some AD and FTD variants are associated with multiple clinical phenotypes and not just dementia. These findings were discussed in the context of causal relationship versus pleiotropy via Mendelian randomization analysis

Oxysterol-binding protein-1 (OSBP1) modulates processing and trafficking of the amyloid precursor protein

Background Evidence from biochemical, epidemiological and genetic findings indicates that cholesterol levels are linked to amyloid-β (Aβ) production and Alzheimer's disease (AD). Oxysterols, which are cholesterol-derived ligands of the liver X receptors (LXRs) and oxysterol binding proteins, strongly regulate the processing of amyloid precursor protein (APP). Although LXRs have been studied extensively, little is known about the biology of oxysterol binding proteins. Oxysterol-binding protein 1 (OSBP1) is a member of a family of sterol-binding proteins with roles in lipid metabolism, regulation of secretory vesicle generation and signal transduction, and it is thought that these proteins may act as sterol sensors to control a variety of sterol-dependent cellular processes. Results We investigated whether OSBP1 was involved in regulating APP processing and found that overexpression of OSBP1 downregulated the amyloidogenic processing of APP, while OSBP1 knockdown had the opposite effect. In addition, we found that OSBP1 altered the trafficking of APP-Notch2 dimers by causing their accumulation in the Golgi, an effect that could be reversed by treating cells with OSBP1 ligand, 25-hydroxycholesterol. Conclusion These results suggest that OSBP1 could play a role in linking cholesterol metabolism with intracellular APP trafficking and Aβ production, and more importantly indicate that OSBP1 could provide an alternative target for Aβ-directed therapeutic.</p

Reliability and Validity of a Home-Based Self-Administered Computerized Test of Learning and Memory Using Speech Recognition

IntroductionThe objective of this study is to evaluate the reliability and validity of the ReVeReTM word list recall test (RWLRT), which uses speech recognition, when administered remotely and unsupervised.MethodsProspective cohort study. Participants included 249 cognitively intact community dwelling older adults. Measures included clinician administered neuropsychological assessments at baseline and unsupervised remotely administered tests of cognition from six time-points over&nbsp;six months.ResultsThe RWLRT showed acceptable validity. Reliability coefficients varied across time points, with poor reliability between times 1 and 2 and fair-to-good reliability across the remaining five testing sessions. Practice effects were observed with repeated administration as expected.DiscussionUnsupervised computerized tests of cognition, particularly word list learning and memory tests that use speech recognition, have significant potential for large scale early detection and long-term tracking of cognitive decline due to AD

, H4 cells stably overexpressing APP (H4-APP) were transfected with OSBP1 cDNA as described in Methods

Cell lysates from untransfected cells and those transiently overexpressing OSBP1 were immunoblotted with antibodies to the C-terminus of APP (upper panel), c-myc (middle panel), which detects the myc-tagged OSBP1, and actin, used for loading control. , OSBP1 overexpression decreased PMA-regulated sAPPα secreted levels. Cells were treated with PMA as described in Methods. Proteins from cell lysates and media were separated by SDS-PAGE and lysates were immunoblotted with anti-myc antibody (upper panel). Media samples were analyzed for sAPPα using the 6E10 antibody (middle panel). Cell lysates were also analyzed for CTFα using an antibody to the C-terminus of APP (lower panel). Densitometric analysis of Western blots is shown on the right. *p < 0.05 and **p < 0.01 by Student's test.<p><b>Copyright information:</b></p><p>Taken from "Oxysterol-binding protein-1 (OSBP1) modulates processing and trafficking of the amyloid precursor protein"</p><p>http://www.molecularneurodegeneration.com/content/3/1/5</p><p>Molecular Neurodegeneration 2008;3():5-5.</p><p>Published online 18 Mar 2008</p><p>PMCID:PMC2323375.</p><p></p