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ApoE4 at the dawn of Alzheimer's disease - Synaptic & endosomal insights

Nyberg, Emma LU (2026) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, and with an aging population, its burden will continue to rise, affecting families and straining societal resources. Biological changes in AD begin decades before symptoms appear, offering a crucial window for therapeutic intervention.
Understanding the underlying mechanisms is essential for preventing or delaying disease onset. APOE4 is the major genetic risk factor for AD, and elucidating its impact in the brain can reveal potential therapeutic targets. In this thesis, we explore the early cellular effects of ApoE4 in AD, focusing on its impact on endosomal and synaptic function.
In paper I, we show that ApoE is internalized into various cell types, but that... (More)
Alzheimer’s disease (AD) is the most common form of dementia, and with an aging population, its burden will continue to rise, affecting families and straining societal resources. Biological changes in AD begin decades before symptoms appear, offering a crucial window for therapeutic intervention.
Understanding the underlying mechanisms is essential for preventing or delaying disease onset. APOE4 is the major genetic risk factor for AD, and elucidating its impact in the brain can reveal potential therapeutic targets. In this thesis, we explore the early cellular effects of ApoE4 in AD, focusing on its impact on endosomal and synaptic function.
In paper I, we show that ApoE is internalized into various cell types, but that trafficking routes differ between them. ApoE internalized by N2A neuroblastoma cells and astrocytes was largely trafficked to lysosomes. However, this did not occur in neurons, where ApoE remained in neurites rather than being transported to the cell bodies. We further showed that ApoE could intersect intracellularly with amyloid β (Aβ) in both N2A cells and neurons. In paper II, we examined how ApoE4 affects endosomal function in primary neurons. At a mature stage, 18 days in vitro (DIV), we could not detect endosomal differences.
However, when the cultures were aged to 25 DIV, ApoE4 neurons showed reduced degradative capacity and a predisposition to accumulate administered cholesterol in their endolysosomes. In paper III, we used primary cultures from APPNL-F mice and showed that synaptic Aβ increased with neuronal aging (between 15 and 25 DIV) and was higher in neurons treated with astrocytic ApoE4 compared to ApoE3.
In paper IV, we evaluated the synaptic profiles of aged ApoE3 and ApoE4 mice in females and males. Lipidomic and proteomic analyses of synaptosomes showed changes with ApoE4 that were both shared and distinct between sexes. In both sexes, ApoE4 was associated with alterations in proteins related to metabolism, trafficking, and Rho GTPase signaling. However, ApoE4 males showed cytoskeleton related changes suggestive of reduced polymerization, as well as lower levels of redox and glucose metabolizing enzymes. In contrast, ApoE4 females exhibited higher levels of triglycerides containing polyunsaturated fatty acids, reduced levels of respiratory complex subunits, and increased levels of enzymes involved in redox balance and glucose metabolism. Together, our research contributes to a better understanding of the neuronal impact of ApoE4 and helps elucidate the cellular mechanisms driving the development of AD. (Less)
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author
supervisor
opponent
  • Adjunct Assistant Professor Ioannou, Maria, Department of Physiology, University of Alberta
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Alzheimer disease, APOE, Neurons, Endosome, Synapses
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2026:81
pages
117 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join via Zoom: https://lu-se.zoom.us/j/63243257581?pwd=hNE5q7ZZD344wGLWkBA2AaxMjzqRLZ.1
defense date
2026-05-25 14:00:00
ISSN
1652-8220
ISBN
978-91-8021-879-5
language
English
LU publication?
yes
id
5a29979c-a03c-4034-900f-78cca5286ea8
date added to LUP
2026-03-23 10:49:38
date last changed
2026-04-30 08:45:56
@phdthesis{5a29979c-a03c-4034-900f-78cca5286ea8,
  abstract     = {{Alzheimer’s disease (AD) is the most common form of dementia, and with an aging population, its burden will continue to rise, affecting families and straining societal resources. Biological changes in AD begin decades before symptoms appear, offering a crucial window for therapeutic intervention. <br/>Understanding the underlying mechanisms is essential for preventing or delaying disease onset. APOE4 is the major genetic risk factor for AD, and elucidating its impact in the brain can reveal potential therapeutic targets. In this thesis, we explore the early cellular effects of ApoE4 in AD, focusing on its impact on endosomal and synaptic function. <br/>In paper I, we show that ApoE is internalized into various cell types, but that trafficking routes differ between them. ApoE internalized by N2A neuroblastoma cells and astrocytes was largely trafficked to lysosomes. However, this did not occur in neurons, where ApoE remained in neurites rather than being transported to the cell bodies. We further showed that ApoE could intersect intracellularly with amyloid β (Aβ) in both N2A cells and neurons. In paper II, we examined how ApoE4 affects endosomal function in primary neurons. At a mature stage, 18 days in vitro (DIV), we could not detect endosomal differences. <br/>However, when the cultures were aged to 25 DIV, ApoE4 neurons showed reduced degradative capacity and a predisposition to accumulate administered cholesterol in their endolysosomes. In paper III, we used primary cultures from APPNL-F mice and showed that synaptic Aβ increased with neuronal aging (between 15 and 25 DIV) and was higher in neurons treated with astrocytic ApoE4 compared to ApoE3. <br/>In paper IV, we evaluated the synaptic profiles of aged ApoE3 and ApoE4 mice in females and males. Lipidomic and proteomic analyses of synaptosomes showed changes with ApoE4 that were both shared and distinct between sexes. In both sexes, ApoE4 was associated with alterations in proteins related to metabolism, trafficking, and Rho GTPase signaling. However, ApoE4 males showed cytoskeleton related changes suggestive of reduced polymerization, as well as lower levels of redox and glucose metabolizing enzymes. In contrast, ApoE4 females exhibited higher levels of triglycerides containing polyunsaturated fatty acids, reduced levels of respiratory complex subunits, and increased levels of  enzymes involved in redox balance and glucose metabolism. Together, our research contributes to a better understanding of the neuronal impact of ApoE4 and helps elucidate the cellular mechanisms driving the development of AD.}},
  author       = {{Nyberg, Emma}},
  isbn         = {{978-91-8021-879-5}},
  issn         = {{1652-8220}},
  keywords     = {{Alzheimer disease; APOE; Neurons; Endosome; Synapses}},
  language     = {{eng}},
  number       = {{2026:81}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{ApoE4 at the dawn of Alzheimer's disease - Synaptic & endosomal insights}},
  url          = {{https://lup.lub.lu.se/search/files/245585182/Podd_avhandling-esv2-50p-bg-10p-music-10p.wav}},
  year         = {{2026}},
}