Mitochondria in Alzheimer disease : regulatory mechanisms and cell death

University dissertation from Stockholm : Karolinska Institutet, Dept of Neurobiology, Care Sciences and Society

Abstract: 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 A? production. In Paper I, we studied this relationship and showed that during caspase activation intracellular A?42/A?40 ratio increases due to caspase cleavage of presenilin 1 (PS1) residing in active ?-secretase complexes. Intracellular A? is cytotoxic and interferes with various processes for example intra-mitochondrial accumulation cause damage to mitochondrial functions. A? 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 ?3/?4 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-? peptide (A?). 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.

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