Browsing by Subject "Cell Adhesion Molecules, Neuronal"
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Item ApoE Receptors in Alzheimer's and CNS Function(2017-03-24) Lane-Donovan, Courtney; Powell, Craig M.; Herz, Joachim; Eisch, Amelia J.; Huber, Kimberly M.Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder and the most common form of dementia over age 65. The predominant genetic risk factor for AD is the ε4 allele of apolipoprotein E (ApoE4). Other genes related to lipid metabolism and lipoprotein receptor signaling have also been identified as risk modifiers for AD. Despite nearly two decades of research, the mechanisms by which lipid transport proteins cause central nervous system (CNS) disease are not completely understood. Here, the ApoE receptor family and its ligands and their roles in CNS function and neurological disease were explored. It has been previously shown that ApoE4 renders neurons resistant to the neuromodulator and ApoE receptor ligand Reelin, which enhances synaptic plasticity and protects against amyloid β (Aβ) oligomer-induced synaptic toxicity in vitro. Here, mice with reduced Reelin expression were more sensitive to amyloid-induced synaptic suppression, and had memory and learning disabilities at very low amyloid levels. However, this effect of Reelin loss did not extend to other forms a neurological insult, since the Reelin conditional knockout mice were not more susceptible to transient middle cerebral artery occlusions. Together, these findings highlight the specific physiological importance of Reelin for protecting the brain against Aβ-induced synaptic dysfunction and memory impairment. One of the continuing debates in the AD field is whether ApoE is required for synaptic function. ApoE knockout mice have synaptic loss; however, they also have severely increased plasma lipids, which could independently contribute to CNS dysfunction. A novel mouse with normal plasma ApoE, but severely depleted brain ApoE, shares a similar synaptic phenotype as ApoE knockout mice, suggesting central ApoE is required for brain function. To determine if diet can modulate ApoE levels, wildtype, ApoE3, and ApoE4 targeted replacement mice were fed a chow, high-fat, or ketogenic (high-fat, very-low-carb) diet. Surprisingly, high-fat diet reduced hippocampal ApoE levels in ApoE3 TR mice, indicating an intersection of genetic (ApoE isoform) and lifestyle (diet) risk factors on AD pathogenesis. Taken together, these findings highlight the importance of ApoE receptors and their ligands in AD biology, and future studies will have to determine how to target these mechanisms to treat AD and improve patient outcomes.Item Does Reelin Affect Recovery from a Stroke?(2016-01-19) DeSai, Charisma; Herz, Joachium; Stowe Ann M.; Lane-Donovan, CourtneyReelin is an extraceullular glycoprotein that modulates synaptic plasticity and increases long-term potentiation. Since Reelin has neuroprotective effects, we were interested to see if Reelin plays a role in recovery after significant neurological damage. Earlier studies with reeler mice showed that mice lacking Reelin have increased susceptibility to stroke and suffer more damage post-stroke. Since Reelin is important in neuronal migration during development, it is possible that the effects seen were due to improper brain development, instead of Reelin deficiency itself. Instead of using Reeler mice, we used the Reelin conditional knockout(cKO) mouse model. Thus, we were able to see the effects of Reelin loss while permitting normal brain development. Stroke size and post-stroke behavior were investigated after inducing transient middle cerebral artery occlusion in four-month-old Reelin cKO mice. No significant difference was seen between wild type and Reelin cKO mice in infarct size or behavior, suggesting that while Reelin does play in important function in the brain, it does not play a significant role in post-stroke recovery.Item Synaptic Cell Adhesion And Functional Architecture Of CNS Synapses(2007-08-08) Atasoy, Deniz; Kavalali, Ege T.Synapses are specialized intercellular junctions through which neurons communicate. The two sides of a synapse are held together with adhesion molecules. We investigated the role of synaptic adhesion molecules neuroligins, neurexins, SynCAM and dystroglycan using overexpression and knock-out mice analysis approaches. We showed that neuroligins mediate validation of synapses in an activity dependent manner and different isoforms of neuroligins mediate different types of synapse validation. We also showed that binding partners of neuroligins, i.e. neurexins, have a cell autonomous effect on inhibitory synapses, independent of neuroligins. Analysis of dystroglycans failed to reveal a significant phenotype in dissociated cultures, whereas SynCAM had a robust synapse inducing role in developing networks. Furthermore we have shown that this effect of SynCAM is mediated through its cytoplasmic interactions. We further investigated cytoplasmic downstream effectors of neurexins and SynCAM by analyzing CASK and Mint proteins using knock-out approaches. We have shown that both CASK and Mints are essential for survival and synaptic function. Our results indicate that synaptic cell adhesion molecules are not merely passive structural elements but actively participate in information transfer and signaling between neurons by interacting with each other and with their intracellular effectors. We have also investigated homeostatic properties of vesicle recycling and we have demonstrated that activity levels of a neuronal network determines the pathways through which synapses replenish the neurotransmitter vesicles during high frequency stimulation. Finally, we explored the relationship between evoked and spontaneous vesicle fusion and their postsynaptic targets using NMDA receptors. We uncovered previously unexpected segregation of receptor pools that respond to spontaneous or evoked vesicle fusion events. Our experiments also revealed that synaptic cleft is not a mere empty space but rather a complex structure filled with various elements can effect diffusion of neurotransmitter and hence information transfer between neurons.