Alzheimer’s disease (AD), a neurodegenerative disorder initially characterized by mild memory impairments, progresses to global cognitive deficits and eventually death. AD pathological hallmarks are plaques and tangles. Acute and chronic effects of familial Alzheimer’s disease (FAD) genes were examined in WT and transgenic mice respectively. We used viral vectors to acutely express FAD genes encoding the Swedish, Indiana, and Swedish and Indiana double mutation, of amyloid precursor protein (APP) in the hippocampal CA1 region (which exhibits early AD pathology) in mice. Acute expression of FAD genes produced deficits in the formation but not retreival of spatial memory. We next examined spine density as changes are thought to affect synaptic plasticity. Acute expression of FAD genes did not affect the structure (dendritic length, intersections and nodes), but decreased spine density in infected CA1 neurons. Amyloid beta (Aβ) binds to excitatory synapses, particularly to GluA2-AMPA receptors (AMPAR) leading to endocytosis. Therefore,, acute CA1 expression of FAD genes produced spatial memory formation deficits mediated by impairments in dendritic spine plasticity and transmission via AMPAR endocytosis. Additionally, infusing GluA2-3Y, a peptide that prevents Aβ induced AMPAR endocytosis in acute and chronic (TgCRND8) AD mouse models expressing double mutated APP genes, was similarly able to rescue the spatial memory and spine density deficits.
Since the transcription factor CREB is critical for normal memory formation across species, we investigated its role in TgCRND8 mice. We observed additional deficits in the dorsal hippocampus of TgCRND8 mice, including 1) biochemistry (CREB activation), 2) neuronal structure, and 3) neuronal network activity. Moreover, locally and acutely increasing CREB function in the CA1 region of TgCRND8 mice was sufficient to restore function in each domain independent of plaque load or aggregated Aβ levels. Together, these studies indicate that targeting GluA2 or CREB may be useful therapeutic strategies in treating AD.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/65495 |
| Date | 20 June 2014 |
| Creators | Yiu, Adelaide Pearl |
| Contributors | Josselyn, Sheena |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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