Fe65-amyloid precursor protein signalling and Alzheimer's disease

• Main Author: Dunbar, Charlotte Emily
• Other Authors: Miller, Christopher ; Noble, Wendy Jane
• Published: King's College London (University of London) 2017
• Subjects: 616.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.702533

Deposition of Aβ in amyloid plaques and accumulation of hyperphosphorylated tau in neurofibrillary 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 Unpublished next generation sequencing of Fe65 knockout mouse brains suggested that Fe65 may affect the wnt signalling pathway, which regulates GSK3β activity.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.