Clinical studies suggest that agonists at peroxisome proliferator-activated receptor gamma (PPARg) may exert beneficial effects in patients with mild-to-moderate Alzheimer's disease (AD), but the mechanism for the potential therapeutic interest of this class of drugs has not yet been elucidated. Here, in mice overexpressing mutant human amyloid precursor protein, we found that chronic treatment with rosiglitazone, a high-affinity agonist at PPARg, facilitated b-amyloid peptide (Ab) clearance. Rosiglitazone not only reduced Ab burden in the brain but, importantly, almost completely removed the abundant amyloid plaques observed in the hippocampus and entorhinal cortex of 13-month-old transgenic mice. In the hippocampus, neuropil threads containing phosphorylated tau, probably corresponding to dystrophic neurites, were also decreased by the drug. Rosiglitazone switched on the activated microglial phenotype, promoting its phagocytic ability, reducing the expression of proinflammatory markers and inducing factors for alternative differentiation. The decreased amyloid pathology may account for the reduction of p-tau-containing neuropil threads and for the rescue of impaired recognition and spatial memory in the transgenic mice. This study provides further insights into the mechanisms for the beneficial effect of rosiglitazone in AD patients.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a major cause of familial Parkinsonism, and the G2019S mutation of LRRK2 is one of the most prevalent mutations. The deregulation of autophagic processes in nerve cells is thought to be a possible cause of Parkinson's disease (PD). In this study, we observed that G2019S mutant fibroblasts exhibited higher autophagic activity levels than control fibroblasts. Elevated levels of autophagic activity can trigger cell death, and in our study, G2019S mutant cells exhibited increased apoptosis hallmarks compared to control cells. LRRK2 is able to induce the phosphorylation of MAPK/ERK kinases (MEK). The use of 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126), a highly selective inhibitor of MEK1/2, reduced the enhanced autophagy and sensibility observed in G2019S LRRK2 mutation cells. These data suggest that the G2019S mutation induces autophagy via MEK/ERK pathway and that the inhibition of this exacerbated autophagy reduces the sensitivity observed in G2019S mutant cells.

Gonadotropin-releasing hormone (GnRH) receptor agonists are extensively used in the treatment of sex hormone-dependent cancers via the desensitization of pituitary gonadotropes and consequent decrease in steroid sex hormone secretion. However, evidence now points to a direct inhibitory effect of GnRH analogs on cancer cells. These effects appear to be mediated via the G␣ i -type G protein, in contrast to the predominant G␣ q coupling in gonadotropes. Unlike G␣ q coupling, G␣ i coupling of the GnRH receptor can be activated by both agonists and antagonists. This unusual pharmacology suggested that the receptor involved in the cancer cells may not be the classical gonadotrope type I GnRH receptor. However, we have previously shown that a functional type II GnRH receptor is not present in man. In the present study, we show that GnRH agonists and selective GnRH antagonists exert potent antiproliferative effects on JEG-3 choriocarcinoma, benign prostate hyperplasia (BPH-1), and HEK293 cells stably expressing the type I GnRH receptor. This antiproliferative action occurs through a G␣ i -mediated activation of stress-activated protein kinase pathways, resulting in caspase activation and transmembrane transfer of phosphatidlyserine to the outer membrane envelope. Structurally related antagonistic GnRH analogs displayed divergent antiproliferative efficacies but demonstrated equal efficacies in inhibiting GnRH-induced G␣ q -based signaling. Therefore the ability of GnRH receptor antagonists to exert an antiproliferative effect on reproductive tumors may be dependent on ligand-selective activation of the G␣ i -coupled form of the type I GnRH receptor.

It is well known that the action of glucose on pancreatic islets results in increased plasma insulin levels. Nevertheless, high blood glucose levels are not solely responsible for increased insulin secretion (for review, see Ref. 1). For example, in 1964 McIntyre et al. (2) demonstrated that intravenous injection of glucose resulted in a smaller insulin release than that resulting from intrajejunal glucose injection, even though the latter produced lower blood glucose levels compared with the former. Hence, glucose-dependent insulin secretion requires a nutrientdependent component, which was believed to be an endocrine transmitter termed an "incretin" (3). It has since been demonstrated that two hormones, glucagon-like peptide-1 and glucosedependent insulinotropic polypeptide, are responsible for the incretin effect (1).The predominant active form of GLP-1 is actually glucagonlike peptide-1(7-36)amide (termed GLP-1 1 throughout this paper), a 30-residue peptide hormone derived from the post-translational modification of proglucagon in intestinal L cells (1). GLP-1 not only increases glucose-dependent insulin secretion (4 -6), but it also decreases glucose-dependent glucagon secretion (7, 8) and decelerates gastric emptying (9). In addition, GLP-1 has been shown to reduce appetite in rats (10) and to stimulate proinsulin gene transcription and biosynthesis in pancreatic ␤-cells (11, 12). The physiological roles of GLP-1 in maintaining blood sugar levels, via a glucose-dependent mechanism, have heightened interest in the GLP-1 receptor (GLP-1R) as a target for glucose-dependent therapeutic agents designed to treat hyperglycemia resulting from diabetes (13,14). Unfortunately, the half-life of GLP-1 itself after subcutaneous injection is very short because of dipeptidyl peptidase IV cleavage of the first 2 N-terminal residues (15), and so future research requires the design of physiologically stable GLP-1R agonists.The venom of the Gila monster Heloderma suspectum contains a mixture of compounds that includes several peptides related in sequence to GLP-1. Two of these, exendin-3 and exendin-4, are 39-amino acid peptides that share ϳ50% sequence identity to GLP-1 itself and are indeed potent GLP-1R agonists (Fig. 1) (16, 17). Interestingly, although GLP-1 affinity is highly sensitive to N-terminal cleavage, exendin-4 can be truncated by up to 8 residues at its N terminus without significant loss of affinity, suggesting that relative to GLP-1, the central and/or C-terminal residues form additional stabilizing contacts with the receptor (15, 18). Nevertheless, the first two amino acids are also essential for the efficacy of exendin peptides because, once removed, the truncated exendin peptides function as antagonists or inverse agonists (16 -19).

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPP wt ) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ 42 ) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ 42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ-independent pathogenic pathways in Alzheimer's disease.

Abstract. Synapse loss occurs early in Alzheimer's disease (AD) and is considered the best pathological correlate of cognitive decline. Ephrins and Eph receptors are involved in regulation of excitatory neurotransmission and play a role in cytoskeleton remodeling. We asked whether alterations in Eph receptors could underlie cognitive impairment in an AD mouse model overexpressing human amyloid-β protein precursor (hAβPP) with familial mutations (hAβPP swe-ind mice). We found that EphA4 and EphB2 receptors were reduced in the hippocampus before the development of impaired object recognition and spatial memory. Similar results were obtained in another line of transgenic AβPP mice, Tg2576. A reduction in Eph receptor levels was also found in postmortem hippocampal tissue from patients with incipient AD. At the time of onset of memory decline in hAβPP swe-ind mice, no change in surface expression of AMPA or NMDA receptor subunits was apparent, but we found changes in Eph-receptor downstream signaling, in particular a decrease in membrane-associated phospho-cofilin levels that may cause cytoskeletal changes and disrupted synaptic activity. Consistent with this finding, Eph receptor activation in cell culture increased phospho-cofilin levels. The results suggest that alterations in Eph receptors may play a role in synaptic dysfunction in the hippocampus leading to cognitive impairment in a model of AD.

The mutation of Asp198 to Asn in the receptor for glucagon-like peptide-1(7^36)amide (GLP-1) had no e¡ect upon GLP-1 a⁄nity whereas substitution with Ala greatly reduced a⁄nity, demonstrating the importance of polarity rather than negative charge at Asp198. However, the Asp198-Ala mutation had less e¡ect upon the a⁄nity of Exendin-4, a peptide agonist that has been shown previously not to require its N-terminus for high a⁄nity. Moreover, the a⁄nity of a truncated GLP-1 analogue lacking the ¢rst eight residues was not a¡ected by the Asp198-Ala mutation, demonstrating that Asp198 is required for maintaining the binding site of the N-terminal region of GLP-1.

G protein-coupled receptors (GPCRs) play pivotal roles in regulating the function and plasticity of neuronal circuits in the nervous system. Among the myriad of GPCRs expressed in neural cells, class II GPCRs which couples predominantly to the Gs-adenylate cyclase-cAMP signaling pathway, have recently received considerable attention for their involvement in regulating neuronal survival. Neuropeptides that activate class II GPCRs include secretin, glucagon-like peptides (GLP-1 and GLP-2), growth hormone-releasing hormone (GHRH), pituitary adenylate cyclase activating peptide (PACAP), corticotropin-releasing hormone (CRH), vasoactive intestinal peptide (VIP), parathyroid hormone (PTH), and calcitonin-related peptides. Studies of patients and animal and cell culture models, have revealed possible roles for class II GPCRs signaling in the pathogenesis of several prominent neurodegenerative conditions including stroke, Alzheimer's, Parkinson's, and Huntington's diseases. Many of the peptides that activate class II GPCRs promote neuron survival by increasing the resistance of the cells to oxidative, metabolic, and excitotoxic injury. A better understanding of the cellular and molecular mechanisms by which class II GPCRs signaling modulates neuronal survival and plasticity will likely lead to novel therapeutic interventions for neurodegenerative disorders.