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Mitochondria in Alzheimer disease : regulatory mechanisms and cell death

thesis
posted on 2024-09-02, 19:01 authored by Louise Hedskog

Synaptic loss is the major correlate for cognitive decline in Alzheimer disease (AD). Processes taking place in the synapses are highly energy demanding and needs strict regulation, which makes the mitochondria and ER crucial at these sites so as to supply energy and spatially regulate intracellular calcium signaling. The ER and mitochondria interact with each other at a highly specialized region of ER called the mitochondria-associated ER membrane (MAM). At the MAM several processes are regulated, including calcium handling, metabolism of glucose, phospholipids and cholesterol as well as apoptosis, all of which are deranged in AD.

The aim of this thesis was to obtain deeper understanding of processes that could be behind mitochondrial dysfunction and caspase activation, and thereby cause synapse loss. Caspases are activated both during normal plasticity and in apoptosis, and their activation is associated with elevated Aβ production.

In Paper I, we studied this relationship and showed that during caspase activation intracellular Aβ42/Aβ40 ratio increases due to caspase cleavage of presenilin 1 (PS1) residing in active γ-secretase complexes. Intracellular Aβ is cytotoxic and interferes with various processes for example intra-mitochondrial accumulation cause damage to mitochondrial functions. Aβ is imported into the mitochondria via the TOM40 pore. A specific polymorphic poly-T variant (rs10524523), in the TOMM40 gene had been postulated to cause earlier disease onset of late-onset AD (LOAD) in APOE ε3/ε4 carriers.

Knowing the importance of TOM40 protein we set out, in Paper II, to investigate the functional implication of this polymorphism. However, we could not identify any deficits in mitochondrial function or morphology. Nevertheless, the mitochondria are evidently affected by AD, as indication include altered calcium homeostasis and metabolism. These alterations can be linked to the MAM region, which is a region scarcely investigated in the brain.

Therefore, in Paper III, studying MAM, we showed that it exists in synapses and is essential for both neuronal and astrocytic survival. Furthermore, we showed that MAM is altered in human AD brain as well as in APPSwe/Lon mice, and is so before the appearance of plaques. Moreover, MAM can be functionally modulated by the amyloid-β peptide (Aβ). Based on evident alterations in mitochondrial function in AD, treatments enhancing mitochondrial resistance could be a promising strategy.

The final study, Paper IV, concerned a potential novel drug, Dimebon (Latrepirdine), intended for treatment of AD. We found it to enhance mitochondrial function both in absence and presence of stress, and, in turn, partially protect cells to maintain cell viability. Since mitochondrial function is essential for synaptic integrity drugs targeting the mitochondria could have disease-modifying effect.

List of scientific papers

I. Louise Hedskog, Camilla A. Hansson Petersen, Annelie I Svensson, Hedvig Welander, Lars O Tjernberg, Helena Karlström, Maria Ankarcrona. γ-Secretase complexes containing caspase-cleaved presenilin-1 increase intracellular Aβ42/Aβ40 Ratio. J Cell Mol Med. Oct 15, 2150-2163 (2011).
https://doi.org/10.1111/j.1582-4934.2010.01208.x

II. Louise Hedskog, Jesper Brohede, Birgitta Wiehager, Catarina Moreira Pinho, Priya Revathikumar, Lena Lilius, Elzbieta Glaser, Caroline Graff, Helena Karlström, Maria Ankarcrona. Biochemical studies of poly-T variants in the Alzheimer disease associated TOMM40 gene. J Alzheimer Dis. May 16 (2012).
https://doi.org/10.3233/JAD-2012-120580

III. Louise Hedskog, Catarina Moreira Pinho, Riccardo Filadi, Laura Hertwig, Birgitta Wiehager, Annica Rönnbäck, Sandra Gellhaar, Anna Sandebring, Marie Westerlund, Caroline Graff, Bengt Winblad, Dagmar Galter, Homira Behbahani, Paola Pizzo, Elzbieta Glaser, Maria Ankarcrona. MAM is essential for neuronal survival and modulated by Alzheimer disease pathology. [Submitted]

IV. Shouting Zhang, Louise Hedskog, Camilla A Hansson Petersen, Bengt Winblad, Maria Ankarcrona. Dimebon (Latrepirdine) enhances mitochondrial function and protects neuronal cells from death. J Alzheimers Dis. 21, 389-402 (2010).
https://doi.org/10.3233/JAD-2010-100174

History

Defence date

2012-09-14

Department

  • Department of Neurobiology, Care Sciences and Society

Publisher/Institution

Karolinska Institutet

Main supervisor

Ankarcrona, Maria

Publication year

2012

Thesis type

  • Doctoral thesis

ISBN

978-91-7457-854-6

Number of supporting papers

4

Language

  • eng

Original publication date

2012-08-24

Author name in thesis

Hedskog, Louise

Original department name

Department of Neurobiology, Care Sciences and Society

Place of publication

Stockholm

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