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

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

Microglial contribution to synaptic uptake in the prefrontal cortex in schizophrenia

Microglia in human post-mortem tissue in schizophrenia patients' brains engulf synaptic material, but not differently to age-matched non-neurological control brains. Also, schizophrenia brains display similar levels of microgliosis to control brains

Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer’s Disease

Abstract Network hyperexcitability is a feature of Alzheimer’ disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APPNL/F). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APPNL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-β plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting interactions of MFG-E8 rescues the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells at least in part via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.</p

Glial contribution to excitatory and inhibitory synapse loss in neurodegeneration

Synapse loss is an early feature shared by many neurodegenerative diseases, and it represents the major correlate of cognitive impairment. Recent studies reveal that microglia and astrocytes play a major role in synapse elimination, contributing to network dysfunction associated with neurodegeneration. Excitatory and inhibitory activity can be affected by glia-mediated synapse loss, resulting in imbalanced synaptic transmission and subsequent synaptic dysfunction. Here, we review the recent literature on the contribution of glia to excitatory/inhibitory imbalance, in the context of the most common neurodegenerative disorders. A better understanding of the mechanisms underlying pathological synapse loss will be instrumental to design targeted therapeutic interventions, taking in account the emerging roles of microglia and astrocytes in synapse remodeling