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From cholesterol to oxidative stress in Alzheimer's disease : a wide perspective on a multifactorial disease

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thesis
posted on 2024-09-02, 21:35 authored by Susanne Akterin

Epidemiological studies have provided evidence that high cholesterol levels in midlife and lack of antioxidants could render people more susceptible to develop AD. The aim of this thesis project was to get a more profound view of how cholesterol and oxidative stress could modify the development of Alzheimer s disease (AD) on the molecular level, by studying mechanisms of signal transduction.

In Paper I we studied the effects of ApoE deficiency in combination with high fat/high cholesterol intake on mouse brain, and found that these two factors have synergistic effect on tau phosphorylation, causing hyperphosphorylation.

In Paper II we used microarray to examine how the expression of individual genes in brain is affected by long-term high fat/high cholesterol diet. We found changes in a limited number of genes, of which several have previously been linked to neurodegenerative processes. We focused our investigation on activityregulated cytoskeletal-associated protein (Arc), that is important for synaptic plasticity and memory. Arc expression was decreased in brains from mice that received a high-fat/high cholesterol diet, as well as in Alzheimer brain. It is likely that this effect was induced by 27-hydroxycholesterol, a cholesterol metabolite that is able to cross the blood-brain barrier.

We went on to study how oxidative stress affects the brain and in Paper III we found that glutaredoxin-1 (Grx1) and thioredoxin-1 (Trx1) are first in line to protect cells against oxidative stress caused by Abeta. Levels of Grx1 and Trx1 were found to be affected in AD brain and this de-regulation could result in activation of apoptosis signal-regulating kinase (ASK)1, with important consequences for Abeta-induced cell death.

The final study concerned thioredoxin-80, a cleavage product of Trx1, earlier found to be produced when Trx1 is oxidized. In Paper IV we found that Trx80 is present in brain, mainly in neurons, that it is produced by cleavage of Trx1, by ADAM10/17 (alpha-secretase), and that the levels were decreased in AD brain. Suggested functions of Trx80 in brain are to protect against Abeta-induced cell death, possibly by regulating apoptosis, by degradation of ASK1.

In conclusion, AD is a heterogeneous disease, affecting many different cellular processes and signaling pathways, a notion that is further supported by the results presented in this thesis. Since we do not yet know the underlying mechanisms for the disease development the study of risk factors is an alternative way of addressing this problem. The field of risk factors for AD has lately developed rapidly, but more effort is needed to understand the underlying mechanisms for the risk modifying effects. Further investigation in this area is needed, and will provide knowledge on how one should live to prevent the development of AD as well as suggest new targets for drug therapy.

List of scientific papers

I. Rahman A, Akterin S, Flores-Morales A, Crisby M, Kivipelto M, Schultzberg M, Cedazo-Minguez A (2005). High cholesterol diet induces tau hyperphosphorylation in apolipoprotein E deficient mice. FEBS Lett. 579(28): 6411-6. Epub 2005 Nov 2
https://pubmed.ncbi.nlm.nih.gov/16288750

II. Mateos L, Akterin S, Gil-Bea FJ, Spulber S, Rahman A, Björkhem I, Schultzberg M, Flores-Morales A, Cedazo-Minguez A (2008). Activity-Regulated Cytoskeleton-Associated Protein in Rodent Brain is Down-Regulated by High Fat Diet in vivo and by 27-Hydroxycholesterol in vitro. Brain Pathol. May 23: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/18503570

III. Akterin S, Cowburn RF, Miranda-Vizuete A, Jimenez A, Bogdanovic N, Winblad B, Cedazo-Minguez A (2006). Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimers disease. Cell Death Differ. 13(9): 1454-65. Epub 2005 Nov 25
https://pubmed.ncbi.nlm.nih.gov/16311508

IV. Akterin S, Gil-Bea F, Mateos L, Lorenzo-Villegas D, Costa S, Avila-Carino J, Sundtsröm E, Holmgren A, Cedazo-Minguez A (2008). The production of thioredoxin-80 from thioredoxin-1 is mediated by alpha secretase and decrease in Alzheimers disease. [Manuscript]

History

Defence date

2008-12-05

Department

  • Department of Neurobiology, Care Sciences and Society

Publication year

2008

Thesis type

  • Doctoral thesis

ISBN

978-91-7409-172-4

Number of supporting papers

4

Language

  • eng

Original publication date

2008-11-14

Author name in thesis

Akterin, Susanne

Original department name

Department of Neurobiology, Care Sciences and Society

Place of publication

Stockholm

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