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Acta Neuropathol (2011) 122:271283 DOI 10.1007/s00401-011-0836-9
ORIGINAL PAPER
Peroxisomal alterations in Alzheimers disease
Jianqiu Kou Gabor G. Kovacs Romana Hftberger Willem Kulik Alexander Brodde
Sonja Forss-Petter Selma Hnigschnabl Andreas Gleiss Britta Brgger Ronald Wanders
Wilhelm Just Herbert Budka Susanne Jungwirth Peter Fischer Johannes Berger
Received: 18 April 2011 / Accepted: 11 May 2011 / Published online: 19 May 2011 The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract In Alzheimers 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 neuro-pathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages III, IIIIV, and VVI, 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 b-oxidation, in cases with stages VVI pathology compared with those modestly affected (stages III). 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 trafcking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical ndings and the amount of neurobrillary tangles (NFT) and neuritic plaques, quantied 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 Aging Neurobrillary tangles Peroxisome
Plasmalogen VLCFA
Introduction
Owing to the increased life expectancy, the number of aging individuals affected by Alzheimers disease (AD) is growing rapidly. Fundamental knowledge has been generated from basic research and familial mutations
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