Synaptic Glutamate Receptor Dysfunction in Tissue and Animal Models of Alzheimer’s Disease
Type of DegreeDissertation
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The complexity of cognitive decline involved in Alzheimer’s disease (AD) warrants a thorough investigation into the molecular mechanism that may hold the basis for the impaired learning and memory. Indeed, certain molecules have been suggested to play significant roles in AD progression. For example it is well known that the two major hallmarks of AD, amyloid beta fragments and hyperphosphorylated tau contribute to the neuropathogenesis of the disease. Another candidate that may play a significant role in AD is the accelerated lysosomal enzymes arising from a dysfunction of these organelles. Additionally, some of the neurotransmitter systems involved in learning and memory are implicated in AD pathogenesis. The most common and well studied neurotransmitter systems are the cholinergic and glutamatergic systems. Indeed, appropriate expression and function of glutamate receptors subtypes N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) are important in cognitive processes. It is possible that all these molecules and systems may work synergistically to execute the cognitive decline observed in AD. However, it is important to unravel the early events that lead to the cascade of neurodegeneration prior to the overt signs of cognitive decline. To study these events, tissue and animal models have been used by several investigators. The model of choice depends on the intended target point in the neuropathological cascade. In the current we utilized hippocampal organotypic slice cultures exhibiting lysosomal dysfunction to study the early events of neurodegeneration. Progressive changes were achieved by treating the slices with lysosomotropic agent chloroquine for 3, 6 and 9 days. We studied the functional properties of glutamate receptors subtypes AMPA and NMDA in hippocampal slices and in isolated synaptosomes at each stage of lysosomal dysfunction. Our results indicate that there is correlation between lysosomal dysfunction and glutamate receptor function. This study also shows that the altered AMPA channel properties after 9 days of chloroquine treatment can be reversed by the nootropic compound ampakine CX516. To complement the in vitro slice model we investigated the early changes in hippocampal glutamatergic function associated with cholinergic denervation in live animals. The functional properties of synaptic AMPA and NMDA receptors, 4 to 6 days after selective medial septum lesioning with immunotoxin 192 IgG-saporin were studied. To correlate this with slice model we examined whether cholinergic denervation is accompanied by lysosomal dysfunction. It is interesting to note that after 4-7 days of medial septal lesions there was suppression of lysosomal function and modifications in AMPA and NMDA receptor mediated synaptic responses. The data suggest that in both in vitro and in vivo models of AD, the early neuropathogenesis is associated with synaptic glutamatergic dysfunction.