The low-density lipoprotein receptor-related protein (LRP) is an abundant neuronal cell surface receptor that regulates amyloid -protein (A) trafficking into the cell. Specifically, LRP binds secreted A complexes and mediates its degradation. Previously, we have shown in vitro that the uptake of A mediated by LRP is protective and that blocking this receptor significantly enhances neurotoxicity. To further characterize the effects of LRP and other lipoprotein receptors on A deposition, an in vivo model of decreased LRP expression, receptor-associated protein (RAP)-deficient (RAPϪ/Ϫ) mice was crossed with human amyloid protein precursor transgenic (hAPP tg) mice, and plaque formation and neurodegeneration were analyzed. We found that, although the age of onset for plaque formation was the same in hAPP tg and hAPP tg/RAPϪ/Ϫ mice, the amount of amyloid deposited doubled in the hAPP tg/RAPϪ/Ϫ background. Moreover, these mice displayed increased neuronal damage and astrogliosis. Together, these results further support the contention that LRP and other lipoprotein receptors might be neuroprotective against A toxicity and that this receptor might play an integral role in A clearance.
This investigation examined receptor subtype specificity and possible modulation by GABAa receptor ligands of NPY-induced behavioral responses to stressful stimuli. First, a series of NPY receptor agonists were examined for their potential effects on punished responding in a conflict test modified for incremental shock. NPY, peptide YY (PYY) and NPY Y1 receptor agonists [Leu31,Pro34]-NPY and [Gly6, Glu26,Lys26,Pro34]-NPY produced increases in punished responding in the conflict test. No significant effects on unpunished responding were noted. The pattern of responding was similar to that observed with the benzodiazepine agonist chlordiazepoxide. Neither pancreatic peptide (PP) nor the Y2 agonists NPY13-36 or [Glu2,32,Ala6,Dpr27,Lys28]-NPY significantly altered punished or unpunished responding. Of significance, the atypical Y1 agonist [Cys7,21,Pro34]-NPY produced negligible effects on punished responding, consistent with the presence of a subclass of Y1 receptors. Second, the anxiolytic effects of NPY were subjected to treatments that block actions at the GABAa receptor complex. The increase in punished responding produced by NPY was not altered by administration of the benzodiazepine antagonist flumazenil and only partially blocked by the picrotoxinin receptor ligand isopropylbicyclophosphate (10 and 15 microg/kg). These findings further support the hypothesis that the pharmacologic substrates for the anxiolytic-like actions of NPY may be mediated by the Y1 receptor subtype and suggest that these actions are independent of either the benzodiazepine or picrotoxinin binding sites of the GABA/benzodiazepine receptor complex.
In order to delineate the neuroprotective role of the low density lipoprotein receptor-related protein (LRP) against amyloid -protein toxicity, studies were performed in C6 cells challenged with amyloid -protein in the presence or absence of activated ␣ 2 -macroglobulin. Toxicity was assessed via two cell viability assays. We found that this endocytic receptor conferred protection against amyloid -protein toxicity in the presence of activated ␣ 2 -macroglobulin and its down-regulation via inhibition by receptor-associated protein or transfection of cells with presenilin 1, increased susceptibility to amyloid -protein toxicity. Increased surface LRP immunoreactivity in response to amyloid -protein challenge was associated with increased translocation of LRP from the endoplasmic reticulum to the surface, rather than from increased mRNA or protein expression. Furthermore, this translocation of LRP to the surface was mediated by a calcium/calmodulin protein kinase II-dependent signaling pathway. These studies provide evidence for a protective role of LRP against amyloid -protein toxicity and may explain the aggressive nature of presenilin-1 mutation in familial Alzheimer's disease. Low density lipoprotein (LDL)1 receptor-related protein (LRP) is a multifunctional endocytic receptor that binds a variety of ligands including apolipoprotein E (apoE)-containing lipoproteins (1, 2), activated ␣ 2 -macroglobulin (*␣ 2 m) complexes, and proteins containing Kunitz-type protease inhibitor domains such as secreted amyloid precursor protein (3). Recent studies have suggested that altered LRP regulation may be an integral component of Alzheimer's disease (AD) pathogenesis (4, 5). Importantly, LRP and its ligands, APP, apoE, and ␣ 2 m, have all been genetically linked to AD (6 -9), and colocalize in senile plaques, a hallmark of AD (4, 10). In addition, patients with probable AD have increased serum levels of LRP ligands including apoE, ␣ 1 -antichymotrypsin, plasmin, and urokinase (11-13), suggesting that LRP expression (or function) may be deficient in these patients. Furthermore, we have previously shown that overexpression of or mutations in the presenilin 1 (PS1) gene, which has been closely linked to the majority of early onset familial AD cases, results in significant down-regulation of LRP (5). Taken together, these data indicate that LRP plays a central role in AD pathogenesis.Although the mechanisms through which LRP might be involved in AD remain unclear, a recent study has suggested a role for LRP in clearance of amyloid -protein (A) (14). Specifically, A is internalized by LRP when bound to apoE or *␣ 2 m (14 -18). Whether this effect is toxic or protective is not completely known. Thus, the main objective of the present study was to determine if addition of an A-binding LRP ligand prevents A toxicity. The results suggest that LRP mediates protection against A toxicity in the presence of *␣ 2 m and that LRP surface expression is preferentially up-regulated in response to A challenge via a calcium/calmod...
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