eprintid: 10101915
rev_number: 27
eprint_status: archive
userid: 608
dir: disk0/10/10/19/15
datestamp: 2020-09-08 14:45:42
lastmod: 2021-07-01 06:10:26
status_changed: 2020-09-08 14:45:42
type: thesis
metadata_visibility: show
creators_name: Podpolny, Marina
title: The role of DKK3 in synapse dynamics in the adult hippocampus and in Alzheimer’s Disease
ispublished: unpub
divisions: UCL
divisions: A01
divisions: B02
divisions: C08
divisions: D09
note: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
abstract: Synaptic loss highly correlates with cognitive decline in Alzheimer’s Disease (AD). Accumulating evidence implicates deregulation of Wnt signalling in AD pathology and synapse dysfunction. Wnt signalling plays an important role in synapse formation during development and synapse plasticity and maintenance in the adult brain. Recent studies showed that Dickkopf-3 (DKK3), an abundantly expressed Wnt antagonist, is elevated in the cerebral spinal fluid and accumulates in Amyloid beta (Aβ) plaques in AD patients. However, the role of DKK3 in the brain is mostly unexplored. I examined the function of DKK3 in mature synapses and in AD by performing gain- and loss-of-function studies, and using biochemical, molecular and imaging techniques. I showed that DKK3 is present in neurons, synapses, and astrocytes of the adult hippocampus. DKK3 gain-of-function leads to a decrease in excitatory to inhibitory (E/I) synapse ratio, whereas loss-of-function of DKK3 leads to an increase in E/I synapse ratio in the hippocampus. Exploring the role of DKK3 in E/I synaptic changes after long-term depression (LTD), I discovered that DKK3 secretion is increased and that DKK3 is required for the E/I synapse reorganisation after NMDAR-mediated LTD. These findings reveal a previously unknown role of DKK3 in regulating E/I synapse density and advances our knowledge of E/I synapse balance regulation in the adult hippocampus. Investigating the role of DKK3 in AD, I found that DKK3 secretion is increased in the J20 hippocampus, which exhibits decreased E/I synapse ratio. In addition, I showed that DKK3 accumulates in dystrophic neurites around plaques and promotes plaque expansion, possibly through microglia regulation. My results suggest that DKK3 contributes to AD pathology by controlling plaques growth and may further contribute by affecting E/I synapse imbalance in the hippocampus. In summary, these results demonstrate a novel mechanism, by which deficient Wnt signalling contributes to synapse vulnerability and pathology in AD.
date: 2020-06-28
date_type: published
oa_status: green
full_text_type: other
thesis_class: doctoral_open
thesis_award: Ph.D
language: eng
thesis_view: UCL_Thesis
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1791145
lyricists_name: Podpolny, Marina
lyricists_id: MTETE37
actors_name: Dewerpe, Marie
actors_id: MDDEW97
actors_role: owner
full_text_status: public
pages: 285
event_title: UCL (University College London)
institution: UCL (University College London)
department: Division of Biosciences
thesis_type: Doctoral
editors_name: Salinas, P
citation:        Podpolny, Marina;      (2020)    The role of DKK3 in synapse dynamics in the adult hippocampus and in Alzheimer’s Disease.                   Doctoral thesis  (Ph.D), UCL (University College London).     Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10101915/1/Marina%20Podpolny-%20FINAL.pdf