Abstract
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Mitochondrial abnormalities have been identified in many cell types in AD, with deficits preceding the development of the classical pathological aggregations. Ursodeoxycholic acid (UDCA), a treatment for primary biliary cirrhosis, improves mitochondrial function in fibroblasts derived from Parkinson's disease patients as well as several animal models of AD and Parkinson's disease. In this paper, we investigated both mitochondrial function and morphology in fibroblasts from patients with both sporadic and familial AD. We show that both sporadic AD (sAD) and PSEN1 fibroblasts share the same impairment of mitochondrial membrane potential and alterations in mitochondrial morphology. Mitochondrial respiration, however, was decreased in sAD fibroblasts and increased in PSEN1 fibroblasts. Morphological changes seen in AD fibroblasts include reduced mitochondrial number and increased mitochondrial clustering around the cell nucleus as well as an increased number of long mitochondria. We show here for the first time in AD patient tissue that treatment with UDCA increases mitochondrial membrane potential and respiration as well as reducing the amount of long mitochondria in AD fibroblasts. In addition, we show reductions in dynamin-related protein 1 (Drp1) level, particularly the amount localized to mitochondria in both sAD and familial patient fibroblasts. Drp1 protein amount and localization were increased after UDCA treatment. The restorative effects of UDCA are abolished when Drp1 is knocked down. This paper highlights the potential use of UDCA as a treatment for neurodegenerative disease.
Highlights
Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the build-up of amyloid plaques and neurofibrillary tangles with a loss of neurons later in the disease course [1]
Mitochondrial function and morphology are altered in both sporadic forms of AD (sAD) and presenilin 1 (PSEN1) patient fibroblasts
Every AD fibroblast line had a significant reduction in mitochondrial membrane potential, ranging from a 35% to an 8% reduction
Summary
Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the build-up of amyloid plaques and neurofibrillary tangles with a loss of neurons later in the disease course [1]. Mounting evidence indicates that amyloid plaques and neurofibrillary tangles do not correlate well with disease severity [2]. Mitochondrial dysfunction is a well-established mechanism in familial and sporadic forms of AD (sAD), with evidence from both post-mortem and peripheral patient tissue as well as animal models. Post-mortem data from AD patients show reduced activity of tricarboxylic acid enzymes and reduced complex IV activity, with complex IV activity decreasing during disease progression [8,9]. Mitochondrial enzymatic failure, reduced glucose metabolism and increased reactive oxygen species production have all been shown to occur before amyloid pathology [10]. Expression of mitochondrial subunits from all respiratory chain complexes is reduced in the entorhinal cortex (which is an area of early pathological change in AD) of AD patients at post-mortem [11].
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