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Emma Nyberg- Institutionen för experimentell medicinsk vetenskap
Title: The early cellular phase of ApoE4 in Alzheimer’s disease
Main supervisor: Gunnar Gouras
Reviewers: Henrik Ahlenius and Karolina Pircs
Abstract
Background
Alzheimer’s disease (AD) is the leading cause of dementia and is a major and growing public health concern globally. Aging and the apolipoprotein E4 (ApoE4) allele are the most important risk factors for the development of AD. ApoE is mainly produced by astrocytes and is the most important lipoprotein in the brain. As the predominant genetic risk factor for AD, ApoE4 plays a pivotal role in better understanding the fundamental cellular pathways implicated in AD development. We hypothesize that there is a complex interplay among ApoE, amyloid-β, lipids, endosomes, neuronal activity, and aging and understanding how these components alongside ApoE4 impact neuronal function could prove crucial in unravelling early cellular events in AD.
Research questions
- How is ApoE intracellularly trafficked within neurons, and does it intersect with amyloid-beta?
- How does ApoE genotype impact endolysosomal function in neurons?
- How does ApoE genotype influence the lipid composition of synapses?
Preliminary results
We have shown that in cell types like neuroblastomas and astrocytes, ApoE was evidently internalized and trafficked to lysosomes. Neurons, however, trafficked ApoE differently. Despite inhibiting lysosomal function by Bafilomycin A1 treatment, ApoE did not undergo lysosomal trafficking to the cell body in neurons; instead, it remained localized in neurites. In both neuroblastoma cells and primary neurons, we observed ApoE and Aβ/β - CTF in the same lysosomal compartments.
Using primary neurons from ApoE3, ApoE4, and ApoE KO mice we show that endosome function in neurons function similarly between the groups, even after prolonged elevation of synaptic activity. However, with longer time in culture, a proxy for neuronal aging, ApoE4 neurons present reduced degradative capacity without altering the appearance of lysosomes (LAMP1+ compartments). Further studies will explore how the reduced degradative capacity influences amyloid-β metabolism and whether there are other factors, such as cholesterol, might trigger an ApoE4-dependent endosomal affect.
Significance
It is demonstrated that AD pathology begins decades before clinical symptoms manifest. It is pivotal to understand the early pathological events to have a chance to prevent disease progression in the future.
Published studies
- Konings SC, Nyberg E, Martinsson I, Torres-Garcia L, Klementieva O, Guimas Almeida C, Gouras GK. Apolipoprotein E intersects with amyloid-β within neurons. Life Sci Alliance. 2023 Jun 8;6(8):e202201887. doi: 10.26508/lsa.202201887. PMID: 37290814; PMCID: PMC10250689.
Om evenemanget
Plats:
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
Kontakt:
emma [dot] nyberg [at] med [dot] lu [dot] se