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Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, Leinonen V, Ito A, Winblad B, Glaser E, Ankarcrona M. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13145-50. PubMed.
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University of Kansas
Mitochondrial dysfunction is an early event observed in the Alzheimer's brain. Recent studies have highlighted the role of mitochondrial Aβ in AD pathogenesis. We and others have demonstrated the presence of Aβ species in the mitochondria of both AD brain and transgenic AD mice overexpressing Aβ. Aβ progressively accumulates in mitochondria and links to mitochondrial malfunction. However, it is unclear how Aβ gets into mitochondria under physiological and pathological conditions. Our previous studies suggest that Aβ can translocate from the endoplasmic reticulum to the mitochondria, as we demonstrated that the addition of brefeldin A, an inhibitor of protein transport from the ER/intermediate compartment, significantly increased accumulation of mitochondrial Aβ. These data suggest that abnormalities in the secretory pathway may trigger pathologic accumulation of Aβ in mitochondria, potentially promoting mitochondrial dysfunction.
The report by Dr. Hansson Petersen and colleagues further demonstrates that Aβ is imported to the mitochondria through the TOM pathway. These studies provide evidence that Aβ is able to get into mitochondria leading to mitochondrial dysfunction. Further, mitochondria may be a potential therapeutic target for treatment of AD. In addition, illustration of the unique systems involved in importation and proteolysis of Aβ in mitochondria may broaden our understanding on the basic biology of mitochondria.
It's interesting that TFAM can prevent age-dependent memory impairment and loss of neuronal function when overexpressed in transgenic mice. Telmisartan increases expression of TFAM and MTOC1 and has been found to prevent cognitive decline following intracerebroventricular injection of Aβ1-40 (1,2).
Perhaps further reason to suspect benefit with Telmisartan therapy in AD and ALS is provided by Baden and colleagues who report that Telmisartan inhibits methylglyoxal induced caspase-3 activation. Methylglyoxal has been implicated in the formation of amyloid plaques and neurofibrillary tangles in AD. Rohn suggests that caspase-cleaved TDP-43 is a major pathological finding in AD (3,4,5).
References:
Sugimoto K, Qi NR, Kazdová L, Pravenec M, Ogihara T, Kurtz TW. Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension. 2006 May;47(5):1003-9. PubMed.
Mogi M, Li JM, Tsukuda K, Iwanami J, Min LJ, Sakata A, Fujita T, Iwai M, Horiuchi M. Telmisartan prevented cognitive decline partly due to PPAR-gamma activation. Biochem Biophys Res Commun. 2008 Oct 24;375(3):446-9. PubMed.
Baden T, Yamawaki H, Saito K, Mukohda M, Okada M, Hara Y. Telmisartan inhibits methylglyoxal-mediated cell death in human vascular endothelium. Biochem Biophys Res Commun. 2008 Aug 22;373(2):253-7. PubMed.
Kuhla B, Lüth HJ, Haferburg D, Boeck K, Arendt T, Münch G. Methylglyoxal, glyoxal, and their detoxification in Alzheimer's disease. Ann N Y Acad Sci. 2005 Jun;1043:211-6. PubMed.
Rohn TT. Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer's disease. Brain Res. 2008 Sep 4;1228:189-98. PubMed.
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