Peroxisomal alterations in Alzheimer’s disease
Open Access
- 19 May 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Neuropathologica
- Vol. 122 (3), 271-283
- https://doi.org/10.1007/s00401-011-0836-9
Abstract
In Alzheimer’s disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I–II, III–IV, and V–VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal β-oxidation, in cases with stages V–VI pathology compared with those modestly affected (stages I–II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology.Keywords
This publication has 43 references indexed in Scilit:
- Multi-dimensional mass spectrometry-based shotgun lipidomics and the altered lipids at the mild cognitive impairment stage of Alzheimer's diseaseBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2010
- Probing HIV-1 Membrane Liquid Order by Laurdan Staining Reveals Producer Cell-dependent DifferencesOnline Journal of Public Health Informatics, 2009
- Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene databaseNature Genetics, 2007
- Mitochondrial dysfunction and oxidative stress in neurodegenerative diseasesNature, 2006
- Docosahexaenoic Acid Protects from Dendritic Pathology in an Alzheimer's Disease Mouse ModelNeuron, 2004
- Dietary fat intake and the risk of incident dementia in the Rotterdam studyAnnals of Neurology, 1997
- Neuropathological stageing of Alzheimer-related changesActa Neuropathologica, 1991
- Oxidative DNA damage caused by persistent peroxisome proliferation: its role in hepatocarcinogenesisMutation research. Reviews in mutation research, 1989
- Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4Nature, 1970
- A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATIONCanadian Journal of Biochemistry and Physiology, 1959