Leu27 insulin-like growth factor-II, an insulin-like growth factor-II analog, attenuates depolarization-evoked GABA release from adult rat hippocampal and cortical slices.

Accumulated evidence suggests that the single transmembrane domain insulin-like growth factor-II/mannose 6-phosphate receptor (IGF-II/M6P or IGF-II receptor) plays an important role in the intracellular trafficking of lysosomal enzymes and endocytosis-mediated degradation of insulin like growth factor (IGF-II). However, the role of this receptor in signal transduction following IGF-II binding remains controversial. In the present study, we revealed that Leu(27)IGF-II, an analog which binds preferentially to the IGF-II receptor, can attenuate K(+)-as well as veratridine-evoked GABA release from the adult rat hippocampal formation. Tetrodotoxin failed to alter the effects of Leu(27)IGF-II on GABA release, thus suggesting the lack of involvement of voltage-dependent Na(+) channels. Interestingly, the effect is found to be sensitive to pertussis toxin (PTX), indicating the possible involvement of a Gi/o protein-dependent pathway in mediating the release of GABA from the hippocampal slices. Additionally, Leu(27)IGF-II was found to attenuate GABA release from frontal cortex but not from striatum. These results, together with the evidence that IGF-II receptors are localized on GABAergic neurons, raised the possibility that this receptor, apart from mediating intracellular trafficking, may also be involved in the regulation of endogenous GABA release by acting directly on GABAergic terminals.

Altered levels and distribution of amyloid precursor protein and its processing enzymes in Niemann-Pick type C1-deficient mouse brains.

Niemann-Pick type C (NPC) disease is an autosomal recessive neurodegenerative disorder characterized by intracellular accumulation of cholesterol and glycosphingolipids in many tissues including the brain. The disease is caused by mutations of either NPC1 or NPC2 gene and is accompanied by a severe loss of neurons in the cerebellum, but not in the hippocampus. NPC pathology exhibits some similarities with Alzheimer's disease, including increased levels of amyloid beta (Abeta)-related peptides in vulnerable brain regions, but very little is known about the expression of amyloid precursor protein (APP) or APP secretases in NPC disease. In this article, we evaluated age-related alterations in the level/distribution of APP and its processing enzymes, beta- and gamma-secretases, in the hippocampus and cerebellum of Npc1(-/-) mice, a well-established model of NPC pathology. Our results show that levels and expression of APP and beta-secretase are elevated in the cerebellum prior to changes in the hippocampus, whereas gamma-secretase components are enhanced in both brain regions at the same time in Npc1(-/-) mice. Interestingly, a subset of reactive astrocytes in Npc1(-/-) mouse brains expresses high levels of APP as well as beta- and gamma-secretase components. Additionally, the activity of beta-secretase is enhanced in both the hippocampus and cerebellum of Npc1(-/-) mice at all ages, while the level of C-terminal APP fragments is increased in the cerebellum of 10-week-old Npc1(-/-) mice. These results, taken together, suggest that increased level and processing of APP may be associated with the development of pathology and/or degenerative events observed in Npc1(-/-) mouse brains.

ß-amyloid-related peptides potentiate K+-evoked glutamate release from adult rat hippocampal slices.

Accumulated evidence indicates that amyloid beta (Abeta) peptides, by interacting with the central glutamatergic system, can lead to degeneration of neurons associated with Alzheimer's disease (AD) pathology. However, very little is currently known about the role of Abeta peptides in the regulation of glutamatergic function in the normal brain. Given the evidence that Abeta peptides are produced constitutively in the normal brain, we investigated the possible association of amyloid precursor protein (APP)-containing neurons with the vesicular glutamatergic transporter-1 (VGluT1) and measured the effects of various Abeta peptides on endogenous glutamate release from adult rat brain slices. Our results showed that VGluT1 immunoreactivity is localized in close apposition to APP neurons, and that exogenous Abeta(1-40), in a dose-dependent (10(-12) to 10(-7)M) manner potently increased K(+)-evoked glutamate release from hippocampal slices. This effect was observed with other Abeta peptides such as Abeta(1-42), Abeta(1-28) and Abeta(25-35), but not with the reverse Abeta(1-40) or Abeta(25-35) sequences. Tetrodotoxin failed to alter the effects of Abeta(1-40) on glutamate release, which suggests the lack of involvement of voltage-dependent Na(+) channels. In addition to the hippocampus, Abeta(1-40) was found to potentiate K(+)-evoked glutamate release from cortical slices, whereas in the striatum the effect did not reach significant levels. These results demonstrate that physiological concentrations of Abeta peptides can regulate the release of glutamate by acting on glutamatergic terminals. Additionally, the evidence that selected regions of the brain are sensitive to Abeta peptides suggests a potential link between the deposition of Abeta and the preferential vulnerability of brain regions observed in AD pathology.

Altered levels and distribution of IGF-II/M6P receptor and lysosomal enzymes in mutant APP and APP + PS1 transgenic mouse brains.

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor participates in the trafficking of lysosomal enzymes from the trans-Golgi network or the cell surface to lysosomes. In Alzheimer's disease (AD) brains, marked up-regulation of the lysosomal system in vulnerable neuronal populations has been correlated with altered metabolic functions. To establish whether IGF-II/M6P receptors and lysosomal enzymes are altered in the brain of transgenic mice harboring different familial AD mutations, we measured the levels and distribution of the receptor and lysosomal enzymes cathepsins B and D in select brain regions of transgenic mice overexpressing either mutant presenilin 1 (PS1; PS1(M146L+L286V)), amyloid precursor protein (APP; APP(KM670/671NL+V717F)) or APP+PS1 (APP(KM670/671NL+V717F)+PS1(M146L+L286V)) transgenes. Our results revealed that levels and expression of the IGF-II/M6P receptor and lysosomal enzymes are increased in the hippocampus and frontal cortex of APP and APP+PS1, but not in PS1, transgenic mouse brains compared with wild-type controls. The changes were more prominent in APP+PS1 than in APP single transgenic mice. Additionally, all beta-amyloid-containing neuritic plaques in the hippocampal and cortical regions of APP and APP+PS1 transgenic mice were immunopositive for both lysosomal enzymes, whereas only a subset of the plaques displayed IGF-II/M6P receptor immunoreactivity. These results suggest that up-regulation of the IGF-II/M6P receptor and lysosomal enzymes in neurons located in vulnerable regions reflects an altered functioning of the endosomal-lysosomal system which may be associated with the increased intracellular and/or extracellular A beta deposits observed in APP and APP+PS1 transgenic mouse brains.

Heterotrimeric G proteins and the single-transmembrane domain IGF-II/M6P receptor: functional interaction and relevance to cell signaling.

The G protein-coupled receptor (GPCR) family represents the largest and most versatile group of cell surface receptors. Classical GPCR signaling constitutes ligand binding to a seven-transmembrane domain receptor, receptor interaction with a heterotrimeric G protein, and the subsequent activation or inhibition of downstream intracellular effectors to mediate a cellular response. However, recent reports on direct, receptor-independent G protein activation, G protein-independent signaling by GPCRs, and signaling of nonheptahelical receptors via trimeric G proteins have highlighted the intrinsic complexities of G protein signaling mechanisms. The insulin-like growth factor-II/mannose-6 phosphate (IGF-II/M6P) receptor is a single-transmembrane glycoprotein whose principal function is the intracellular transport of lysosomal enzymes. In addition, the receptor also mediates some biological effects in response to IGF-II binding in both neuronal and nonneuronal systems. Multidisciplinary efforts to elucidate the intracellular signaling pathways that underlie these effects have generated data to suggest that the IGF-II/M6P receptor might mediate transmembrane signaling via a G protein-coupled mechanism. The purpose of this review is to outline the characteristics of traditional and nontraditional GPCRs, to relate the IGF-II/M6P receptor's structure with its role in G protein-coupled signaling and to summarize evidence gathered over the years regarding the putative signaling of the IGF-II/M6P receptor mediated by a G protein.

Birth insults involving hypoxia produce long-term increases in hippocampal [125I]insulin-like growth factor-I and -II receptor binding in the rat.

Insulin-like growth factors-I and -II and insulin are structurally related mitogenic growth factors with multiple actions in the developing nervous system and adult CNS. Previous studies have demonstrated acute induction of insulin-like growth factors and their receptors, over a time course of several days, in response to hypoxic/ischemic insult to developing or adult brain. The current study tested whether birth insults involving hypoxia may produce long term changes in brain insulin-like growth factor or insulin receptor levels, lasting into adulthood. For this, rats were born vaginally (controls), by cesarean section, or by cesarean section with 15 min of added global anoxia (cesarean section+anoxia), and brain [125I]insulin-like growth factor-I, [125I]insulin-like growth factor-II and [125I]insulin receptor binding sites were assessed autoradiographically at adulthood. [125I]Insulin-like growth factor-I receptor binding sites were increased in all hippocampal subfields (CA1-CA3, dentate gyrus) in rats born either by cesarean section or by cesarean section+anoxia, compared with vaginal birth. [125I]Insulin-like growth factor-II binding was increased in all hippocampal subfields only in rats born by cesarean section+anoxia compared with either vaginal birth or cesarean section groups. [125I]Insulin-like growth factor-I and [125I]insulin-like growth factor-II binding in frontal cortex, striatum and cerebellum were unaffected by birth group, except for increased [125I]insulin-like growth factor-I binding in the cerebellar molecular layer of cesarean-sectioned animals. Birth group had no significant effect on [125I]insulin binding in any brain region. Affinity cross-linking experiments performed with hippocampal membranes from the three birth groups showed that i) [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II recognized bands of molecular weights characteristic of insulin-like growth factor-I and insulin-like growth factor-II receptors, respectively, and ii) [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II were displaced more potently by their respective unlabeled ligands than by related molecules. It is concluded that birth insults involving hypoxia can induce lasting increases in insulin-like growth factor-I and -II receptors in the CNS. There is specificity with respect to the subtype of insulin-like growth factor receptor affected by the particular birth insult and the brain region affected. It is suggested that enduring increases in levels of insulin-like growth factor receptors consequent to hypoxic birth insult may help to maintain hippocampal function at adulthood, and could modulate responsiveness to insulin-like growth factor administration.