Apolipoprotein E and propagation of pathological tau in Alzheimer’s Disease
Alzheimer’s Disease (AD) is characterised by accumulation of amyloid-b (Ab) in plaques and hyperphosphorylated tau in neurofibrillary tangles. This occurs alongside neuroinflammation and neurodegeneration. Clinically, AD is typified by cognitive decline. Pathological tau propagates through the AD brain in a defined manner, with indications this occurs trans-synaptically. Spread of pathological tau correlates with synapse loss and cognitive decline. Neuroinflammation, contributes to AD pathogenesis and is mediated by glia. Apolipoprotein E (APOE) genotype is the strongest genetic risk factor for the late-onset AD, with APOE4 increasing risk and APOE2 conferring protection. The exact mechanisms by which APOE modulates AD risk remain to be comprehensively discerned. APOE influences Ab pathology, but distinct roles in neurodegeneration and Ab-independent mechanisms are less clear. A systematic literature review was performed to assess APOE effects on neurodegeneration, neuroinflammation and spread of pathological proteins in AD. We identified isoform-specific roles for APOE in neurodegeneration and neuroinflammation. APOE likely mediated some interplay between these processes. We also identified the need for multiple approaches to understand the complex and multifaceted role of APOE in AD pathogenesis. No studies directly investigated whether APOE genotype impacts tau propagation. The trans-synaptic hypothesis of tau spread requires pathological tau to be located at synapses in human brain. This thesis characterised the synaptic localisation of misfolded tau in control and AD human post-mortem brain and analysed this in the context of APOE genotype. Misfolded tau was present at synaptic pairs and was increased in AD brain. Thus, trans-synaptic spread is credible in human AD. Asymmetric distribution of tau across synapses suggested an anterograde mode of transmission, while presence at both synaptic terminals suggested tau propagates across intact synapses. APOE4 did not affect synapse loss but did impact synapse volume. Control APOE4 carriers exhibited similar phenotypes to AD cases, suggesting APOE4 effects on synaptic tau, and potential downstream effects on trans-synaptic spread, occur early in AD. Astrocytes have been implicated in synapse loss and tau propagation in model systems. Whether this translates to human brain is unclear. APOE is produced by glia and isoform-specific effects on neuroinflammation have been identified. Thus, APOE genotype could influence glial contributions to synapse loss and spread of tau in AD. Astrocytes in human post-mortem brain colocalised with presynaptic material, phosphorylated tau and tau-containing presynapses. Greater colocalisation was observed in AD brain and in APOE4 carriers. Thus, in AD, presynapses and pathological tau appeared more prone to astrocytic internalisation, possibly influencing synapse loss and tau spread. APOE4 mainly increased colocalisation in control cases, suggesting APOE effects occur early in AD pathogenesis. These studies suggested APOE effects on AD pathogenesis occur early in disease, before symptom onset. To directly investigate whether APOE genotype impacts tau propagation, mice expressing human APOE isoforms or no APOE were used. Mutant human tau was expressed in the entorhinal cortex by viral-mediated gene delivery and tau propagation quantified. Human tau spread locally and through hippocampal circuits, supporting the trans-synaptic hypothesis of tau propagation. APOE genotype did not influence the spread of pathological tau, although low statistical power impeded robust conclusions being drawn. The findings presented in this thesis demonstrate that trans-synaptic tau spread occurs in a mouse model and is credible in the context of human AD. Moreover, astrocytes might impact tau spread and synapse loss by internalising pathological tau and synapses. APOE4 worsened these phenotypes, particularly in controls, suggesting APOE effects might be particularly relevant early in disease pathogenesis. However, this was not found to be evident in a mouse model of tau propagation. Understanding isoform-specific effects of APOE on tau pathology and glial processes will be instrumental in furthering our understanding of disease mechanisms that could be therapeutically targeted.