Apolipoprotein E and propagation of pathological tau in Alzheimer’s Disease
View/ Open
Date
07/12/2021Author
Davies, Caitlin
Metadata
Abstract
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.