Effects of Heparin and Enoxaparin on APP Processing and Aβ Production in Primary Cortical Neurons from Tg2576 Mice

Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice

Multiple axon guidance cues establish the olfactory topographic map: how do these cues interact?

Each primary olfactory neuron stochastically expresses one of similar to1000 odorant receptors. The total population of these neurons therefore consists of similar to1,000 distinct subpopulations, each of which are mosaically dispersed throughout one of four semi-annular zones in the nasal cavity. The axons of these different subpopulations are initially intermingled within the olfactory nerve. However, upon reaching the olfactory bulb, they sort out and converge so that axons expressing the same odorant receptor typically target one or two glomeruli. The spatial location of each of these 1800 glomeruli are topographically-fixed in the olfactory bulb and are invariant from animal to animal. Thus, while odorant receptors are expressed mosaically by neurons throughout the olfactory neuroepithelium their axons sort out, converge and target the same glomerulus within the olfactory bulb. How is such precise and reproducible topographic targeting generated? While some of the mechanisms governing the growth cone guidance of olfactory sensory neurons are understood, the cues responsible for homing axons to their target site remain elusive

Expression of neurexin ligands, the neuroligins and the neurexophilins, in the developing and adult rodent olfactory bulb

The neurexins are a large family of neuronal cell-surface proteins believed to be involved in intercellular signalling and the formation of intercellular junctions. To begin to assess the role of these proteins in the olfactory bulb, we describe here the expression patterns of their transmembrane and secreted ligands, the neuroligins and neurexophilins, during both embryonic and postnatal development. In situ hybridisation showed that neuroligin 1 and 2 were expressed by second order mitral cells during early postnatal development but not in adults. The secreted ligand for a-neurexin, neurexophilin 1, was also expressed in the postnatal olfactory bulb. Neurexophilin 1 was detected in only periglomerular cells during the early postnatal period of glomerular formation but later was also expressed in mitral cells. These results suggest that neurexin-ligand interactions may be important for development and/or maturation of synaptic connections in the primary olfactory pathway

EXPRESSION OF THE AMYLOID PROTEIN-PRECURSOR OF ALZHEIMERS-DISEASE IN THE DEVELOPING RAT OLFACTORY SYSTEM

The expression of the amyloid protein precursor (APP) of Alzheimer's disease (AD) was examined in the olfactory system of the developing rat. Two monoclonal antibodies were used to detect APP: Alz-90, which specifically recognizes APP, and 22C11 which recognizes both APP and the structurally related protein APLP-2. Very similar patterns of immunoreactivity were observed with both antibodies. APP immunoreactivity was first detected in a subpopulation of olfactory epithelial cells at embryonic day 16 (E16), at a time when primary sensory olfactory axons are first beginning to pierce the glia limitans of the olfactory bulb. At E16, there were more olfactory receptor neurons which expressed APP than the olfactory marker protein (OMP), indicating that some APP-containing neurons were not fully mature. Between E16 and postnatal day 8 (P8), there was a marked increase in the number of primary sensory olfactory neurons expressing APP. In the olfactory bulb, APP was first detected in the mitral cell layer at E18, at a time when synapses are first beginning to form between the dendrites of these cells and primary sensory axons. The level of APP detected within mitral cell perikarya decreased after birth and could no longer be detected between P3 and P8. This indicated that once synaptic connections had been initiated within olfactory glomeruli, the expression of APP within the mitral cells was down-regulated. High levels of APP were, however, detected within the olfactory nerve fiber layer and glomeruli between P3 and P8. The results demonstrate that APP expression in the olfactory system is coordinately regulated with the major periods of synaptogenesis. Since APP is a known neurite outgrowth promoting molecule, we suspect that it may play an important regulatory role in terminal sprouting during synaptogenesis in the olfactory bulb

Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members

The Alzheimer's disease β-amyloid precursor protein (APP) is a member of a larger gene family that includes the amyloid precursor-like proteins, termed APLP1 and APLP2. We previously documented that APLP2(−/−)APLP1(−/−) and APLP2(−/−)APP(−/−) mice die postnatally, while APLP1(−/−)APP(−/−) mice and single mutants were viable. We now report that mice lacking all three APP/APLP family members survive through embryonic development, and die shortly after birth. In contrast to double-mutant animals with perinatal lethality, 81% of triple mutants showed cranial abnormalities. In 68% of triple mutants, we observed cortical dysplasias characterized by focal ectopic neuroblasts that had migrated through the basal lamina and pial membrane, a phenotype that resembles human type II lissencephaly. Moreover, at E18.5 triple mutants showed a partial loss of cortical Cajal Retzius (CR) cells, suggesting that APP/APLPs play a crucial role in the survival of CR cells and neuronal adhesion. Collectively, our data reveal an essential role for APP family members in normal brain development and early postnatal survival