Evidence shows that diabetes increases the risk of developing Alzheimer's disease (AD). Many efforts have been done to elucidate the mechanisms linking diabetes and AD. To demonstrate that mitochondria may represent a functional link between both pathologies, we compared the effects of AD and sucrose-induced metabolic alterations on mouse brain mitochondrial bioenergetics and oxidative status. For this purpose, brain mitochondria were isolated from wild-type (WT), triple transgenic AD (3xTg-AD), and WT mice fed 20% sucrose-sweetened water for 7 months. Polarography, spectrophotometry, fluorimetry, high-performance liquid chromatography, and electron microscopy were used to evaluate mitochondrial function, oxidative status, and ultrastructure. Western blotting was performed to determine the AD pathogenic protein levels. Sucrose intake caused metabolic alterations like those found in type 2 diabetes. Mitochondria from 3xTg-AD and sucrose-treated WT mice presented a similar impairment of the respiratory chain and phosphorylation system, decreased capacity to accumulate calcium, ultrastructural abnormalities, and oxidative imbalance. Interestingly, sucrose-treated WT mice presented a significant increase in amyloid β protein levels, a hallmark of AD. These results show that in mice, the metabolic alterations associated to diabetes contribute to the development of AD-like pathologic features.
The authors’ work is supported by the Fundação para a Ciência e a Tecnologia (FCT) and Fundo Europeu de Desenvolvimento Regional (PTDC/SAU- NEU/103325/2008) and Quadro de Referência Estratégico Nacional (QREN DO-IT).
C.C. has a PhD fellowship from FCT (SFRH/BD/43965/2008).
No potential conflicts of interest relevant to this article were reported.
C.C. researched data, contributed to discussion, and wrote the manuscript. S.C., S.C.C, R.X.S., and I.B. researched data. M.S.S., C.R.O., and P.I.M. contributed to discussion and reviewed and edited the manuscript. P.I.M. is the guarantor of
this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
The authors are sincerely grateful to Dr. Frank LaFerla, from the University of California, for the gift of 3xTg-AD mice and the corresponding WT mice.
- Alzheimer Disease/genetics
- Diabetes Complications/genetics
- Diabetes Mellitus, Type 2/complications
- Electron Transport
- Energy Metabolism
- Gene Expression Regulation
- Mice, Transgenic
- Mitochondria/drug effects
- Mitochondrial Membrane Transport Proteins/drug effects
- Oxidative Stress
- Random Allocation
- Sucrose/adverse effects
- Vitamin E/metabolism