Glial contribution to synaptic ingestion in Alzheimer's disease and schizophrenia

Abstract

The adaptive and plastic nature of synapses allows the brain to perform complex cognitive tasks, like memory formation and retention. A multitude of disorders affecting the central nervous system are associated with the dysfunction and loss of synapses. These include dementia disorders, schizophrenia, multiple sclerosis, and motor neuron disease. Alzheimer’s disease (AD) is the most common form of dementia and is a progressive neurodegenerative disease that affects the elderly population. An estimated 46.8 million people had AD in 2015, with these numbers expecting to reach 75 million people by 2030 due to the increasing life-expectancy of people, and growing population. Neurodegeneration in the AD brain can occur as loss of neurons and synapses, with the latter being the strongest pathological correlate to cognitive decline in AD. There are currently no effective treatments to halt disease progression nor provide curative effects. Therapeutic interventions in mice, although promising, have failed to translate to humans, leading to a reproducibility crisis in the field of AD research. Adding to this low success rate is the fact that the majority of clinical interventions have focused on reducing the levels of one of the hallmark protein aggregates found in the AD brain, amyloid-β (Aβ). It is now becoming apparent that reducing Aβ levels late in disease is not a successful strategy in halting neurodegeneration and the field has opened its windows to new avenues. Research into non-neuronal cells and their response to AD has emerged as a promising target to resolve AD-related pathologies. For instance, microglia are immune cells in the brain, resembling in morphology and function peripheral macrophages, that have emerged as central players in AD pathogenesis. Specifically, some of the ways that microglia contribute to homeostasis are by regulating neuroinflammation, clearing debris by phagocytosis, and aiding the formation of myelin sheaths. Synapse numbers during development are also adjusted when microglia phagocytose less active ones, in a controlled manner. However, recent evidence from animal models of AD has demonstrated that there is excessive phagocytosis of synapses in the AD brains, and points to microglia as a contributor to synapse loss, leading to the progressive cognitive decline. Currently, there is little evidence to support these findings in human brains, and given the problem of reproducibility in the AD field, it is crucial to investigate whether this applies to humans prior to any therapeutic targets going to clinical trials. This doctoral thesis has shown that microglia in the human brain ingest more synapses in AD compared to aged controls and that this process is exacerbated near Aβ plaques. Moreover, isolated pHrodo-tagged synaptoneurosomes from AD and control brains were given to human and mouse microglia and astrocytes in-vitro, and were live imaged in a phagocytosis assay. AD-synaptoneurosomes were ingested both more and faster than control synaptoneurosomes, suggesting disease-related alterations to the synaptic preparations makes them more prone to elimination. From a previous proteomic analysis in the lab, it is known that such signals include complement proteins that are upregulated in AD synapses. Mechanistic studies are now ongoing to determine whether the increased phagocytosis of synapses can be modulated by targeting these synaptic changes. Of note, schizophrenia is a psychiatric disorder affecting the mood and personality, where reduced synaptic levels have also been reported. Schizophrenia brains were examined similarly to AD brains, but in this case no significant differences were found between schizophrenia and control brains, suggesting different disease processes affect synapses. Therefore, is it likely that the progressive synapse loss in AD reflects the increased synaptic ingestion, unlike schizophrenia. Hypothesis: The hypothesis of this thesis is that glial cells contribute to exacerbated synapse loss in the AD and schizophrenia brains by actively removing synapses from brain, and it is predicted that they use opsonin tags on the synapses to induce this change in synaptic ingestion.