Journal
CURRENT ALZHEIMER RESEARCH
Volume 14, Issue 12, Pages 1327-1334Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205014666170505095921
Keywords
Alzheimer's disease; mitochondria; mitochondrial phosphorylation; hypometabolism; gene expression; frontal cortex; entorhinal cortex
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Funding
- Ministerio de Ciencia e Innovacion, Instituto de Salud Carlos III - Fondos FEDER [FIS PIE14/00034, PI14/00757]
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Background: It is well established that mitochondrial damage plays a role in the pathophysiology of Alzheimer's disease (AD). However, studies carried out in humans barely contemplate regional differences with disease progression. Objective: To study the expression of selected nuclear genes encoding subunits of the mitochondrial complexes and the activity of mitochondrial complexes in AD, in two regions: the entorhinal cortex (EC) and frontal cortex area 8 (FC). Methods: Frozen samples from 148 cases processed for gene expression by qRT-PCR and determination of individual activities of mitochondrial complexes I, II, IV and V using commercial kits and home-made assays. Results: Decreased expression of NDUFA2, NDUFB3, UQCR11, COX7C, ATPD, ATP5L and ATP50, covering subunits of complex I, II, IV and V, occurs in total homogenates of the EC in AD stages V-VI when compared with stages I-II. However reduced activity of complexes I, II and V of isolated mitochondria occurs as early as stages I-II when compared with middle-aged individuals in the EC. In contrast, no alterations in the expression of the same genes and no alterations in the activity of mitochondrial complexes are found in the FC in the same series. Conclusion: Different mechanisms of impaired energy metabolism may occur in AD, one of them, represented by the EC, is the result of primary and early alteration of mitochondria; the other one is probably the result, at least in part, of decreased functional input and is represented by hypometabolism in the FC in AD patients aged 86 or younger. HIGHLIGHTS Selected genes encoding subunits of mitochondrial complexes are down- regulated in the entorhinal cortex (EC) but not in the frontal cortex (FC) in AD Reduced activity of complexes I, II and V occurs in the EC but not in the FC in AD Reduced mitochondrial activity in EC occurs as early as stages I-II Altered mitochondrial metabolism in EC can be considered primary in contrast to hypometabolism in FC which is probably related to decreased connectivity input.
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