Abstract
Deposition of Aβ in amyloid plaques and accumulation of hyperphosphorylated tau inneurofibrillary tangles are hallmark pathologies of Alzheimer’s disease. Changes in
APP processing alter Aβ generation and are likely to affect APP function, which may
also contribute to Alzheimer’s disease. APP binds to adaptor protein Fe65 and one
proposed function of this complex is to signal to the nucleus to regulate gene
transcription. However, the mechanisms that regulate APP-Fe65 binding and the
genes regulated by this pathway are poorly understood. Phosphorylation is a common
mechanism for regulating protein-protein interactions and Fe65 is phosphorylated by
several kinases, including ERK1/2. The first hypothesis investigated in this thesis is
that BDNF signalling, which leads to ERK1/2 activation, stimulates Fe65
phosphorylation to regulate its binding to APP. BDNF was found to induce
ERK1/2-dependent phosphorylation of Fe65 and, in a variety of assays including the
use of phosphomutants, BDNF-induced phosphorylation of Fe65 was shown to inhibit
the binding of Fe65 to APP. Unpublished next generation sequencing of Fe65 knockout
mouse brains suggested that Fe65 may affect the wnt signalling pathway, which
regulates GSK3β activity. GSK3β is a kinase involved in the hyperphosphorylation of
tau in Alzheimer’s disease. The second hypothesis tested in this thesis is that Fe65
regulates genes that are linked to GSK3β activity and tau phosphorylation. RT-qPCR
carried out on Fe65 knockout mouse brains and siRNA-treated rat cortical neurons
found that expression of wnt receptor Fzd-1 was affected by loss of Fe65. Additionally,
loss of Fe65 decreased both GSK3β activity and tau phosphorylation. These results
show that Fe65 is involved with APP to function in a key process that can be regulated
by BDNF, a treatment previously shown to be neuroprotective in Alzheimer’s disease
models. Furthermore, they reaffirm the link between APP and Fe65 and link Fe65 to
tau phosphorylation, which may be the first step in understanding the relationship
between the two hallmark pathologies of Alzheimer’s disease.
Publications in refereed journals arising from work undertaken in this PhD:
Cheung, H.N.M., Dunbar, C., Mórotz, G.M., Cheng, W.H., Chan, H.Y.E., Miller, C.C.J.,
Lau, K.-F., 2014. FE65 Interacts with ADP-Ribosylation Factor 6 to Promote Neurite
Outgrowth. The FASEB Journal 28, 337–349.
| Date of Award | 2017 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Christopher Miller (Supervisor) & Wendy Noble (Supervisor) |