Impact Of Alpha-Synuclein Aggregates On Synaptic Structure In The Amygdala

Authors

• Nolwazi Zakithi Gcwensa, University of Alabama at Birmingham

Advisor(s)

Laura Volpicelli-Daley

Committee Member(s)

Alexa Mattheyses
Andrew Arrant
Hong-Yuan Chu
Jeremy Herskowitz
Rita Cowell

School

Joint Health Sciences (Interdisciplinary)

Document Type

Dissertation

Department (new version)

Neurobiology

Date of Award

9-9-2024

Abstract

Parkinson’s disease is the most common motor neurodegenerative and is characterized by intracellular inclusions of misfolded protein α-synuclein termed Lewy Pathology. At least 80% of PD sufferers also experience non-motor symptoms along with, and sometimes preceding, the motor symptoms. Symptoms such as apathy, hallucinations, anxiety and depression could be caused by α-synuclein inclusions causing dysfunction in the amygdala. Lewy pathology in the amygdala of PD patients is robust and has also been observed in a number of other diseases like Dementia with Lewy Bodies and Alzheimer's disease. In our lab, we have shown that using preformed fibrils to induce α-synuclein aggregation in the amygdala of mice results in robust inclusion formation in excitatory neurons within the amygdala. We have also shown that this α-synuclein inclusion formation corresponds with a significant reduction in contextual fear conditioning, related to the basolateral amygdala (BLA). Other labs have shown that α-synuclein aggregation in the amygdala corresponds with defects in cortico-BLA transmission suggesting changes in synaptic architecture as a mechanism by which α-synuclein inclusions could cause behavioral defects within the amygdala. In human aging, increases in synapse size has been demonstrated, and has been observed to be higher in aged people with dementia. It has been hypothesized that synapses may increase in size as a compensative mechanism related to aging and disease. In this work, we show that cortico-BLA synapses are increased in volume under pathological burden in at early time points. We also show that synapses containing α-synuclein inclusions are specifically vulnerable to changes in morphology. Finally, we show that synaptic vesicles have a significantly reduced intervesicular distance in the BLA of mice injected with preformed fibrils compared to controls. Microglial activation and synapse pruning have also recently been shown to play a role in synapse degeneration in neurodegenerative disease. Microglia, the resident macrophage of the central nervous system, have been demonstrated to become activated in Parkinson’s Disease. Microglia are able to prune aberrant synapses in response to changes in synaptic transmission, chemical signaling or complement deposition. In this work we define the glial response to α-synuclein inclusion formation by showing increased number of IBA1+ microglia with de-ramified processes and an increase in expression of CD68, a protein marker of activated macrophages, at early time points. However, we show that this microgliosis response is not sustained with time. We also show increased interaction between non-reactive microglia and synapses, and we also show that microglia preferentially engulf synapses that have enlarged volumes suggesting that quiescent microglia may participate in clearance of aberrant, enlarged synapses at time points preceding cell death. This work shows that α-synuclein inclusion formation induces morphological changes in synapses which may be related to α-synuclein’s role in synaptic vesicle organization. We also show that synaptic loss observed at late time points in the BLA may be mediated by increased interaction between non-reactive microglia and synapses at early time points and not activated microglia as initially hypothesized. Further understanding the relationship between microglia and synapses at early time points in the BLA could have important implications for developing disease modifying therapeutic strategies to manage non-motor symptoms related to amygdala dysfunction in disease.

ProQuest ID

https://proquest.com/docview/3101851067