Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer's Disease.
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.
['Bell|Simon M|SM|', 'Barnes|Katy|K|', 'Clemmens|Hannah|H|', 'Al-Rafiah|Aziza R|AR|', 'Al-Ofi|Ebtisam A|EA|', 'Leech|Vicki|V|', 'Bandmann|Oliver|O|', 'Shaw|Pamela J|PJ|', 'Blackburn|Daniel J|DJ|', 'Ferraiuolo|Laura|L|', 'Mortiboys|Heather|H|']
D000544:Alzheimer Disease D034281:Dynamins D005347:Fibroblasts D020558:GTP Phosphohydrolases D006801:Humans D008869:Microtubule-Associated Proteins D008928:Mitochondria D063154:Mitochondrial Dynamics D024101:Mitochondrial Proteins D010641:Phenotype D053764:Presenilin-1 D014580:Ursodeoxycholic Acid
UDCA treatment mitochondrial morphology neurodegeneration presenilin