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Investigating the Mechanisms Underlying Synaptic and Cognitive Deficits in 慣-Synucleinopathies
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Investigating the Mechanisms Underlying Synaptic and Cognitive Deficits in 慣-Synucleinopathies. |
| 개인저자 | Singh, Balvindar. |
| 단체저자명 | University of Minnesota. Neuroscience. |
| 발행사항 | [S.l.]: University of Minnesota., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 212 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781085736367 |
| 학위논문주기 | Thesis (Ph.D.)--University of Minnesota, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Lee, Michael K. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically related 慣-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. While 慣-synuclein (慣S) abnormalities are directly implicated in PDD and DLB pathogenesis, it is unknown how 慣S contributes to memory loss.Previously, we found that familial Parkinson's disease (PD)-linked human mutant A53T 慣S causes aberrant mislocalization of tau to dendritic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the progressive postsynaptic and memory deficits observed in a mouse model of alpha-synucleinopathy (TgA53T) are mediated by tau. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau-/-) completely ameliorates cognitive dysfunction and concurrent synaptic deficits. Memory deficits in TgA53T mice were also associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau-/- mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results implicate tau as a mediator of human mutant A53T 慣S-mediated abnormalities and suggest a mechanism for memory impairment that occurs via synaptic dysfunction rather than synaptic or neuronal loss.Fibrillar species of 慣S have also recently been implicated as a pathogenic component of synucleinopathies, capable of transmission between neurons and brain regions including the hippocampus. However, how 慣S fibrils impact hippocampal function and contribute to memory deficits are not well understood. We hypothesized that 慣S fibril-induced synaptic changes could be mediated through interactions with other proteins, including tau. Primary hippocampal neurons acutely exposed to fibrillar 慣S species display tau missorting to dendritic spines and both pre and postsynaptic electrophysiological deficits. However, some of these findings may be a product of concentration-dependent fibril-induced spine collapse. Importantly, the pathways behind fibril-mediated tau missorting and synapse loss could be differentiated in vitro. Taken together, these studies suggest that pathological 慣S fibrils and aggregates may act through distinct intracellular and extracellular mechanisms to contribute to neuronal dysfunction and neuronal toxicity.These approaches and results collectively indicate that pathological mutant and aggregated species of 慣S can drive synaptic deficits and represent potential therapeutic targets for amelioration of memory deficits in 慣-synucleinopathies. |
| 일반주제명 | Biology. Health sciences. Medicine. |
| 언어 | 영어 |
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