The results of the trial of Coenzyme Q10 in Parkinson's patients are very encouraging and provide a rationale for longer-term therapy. There is a solid basis for believing that CoQ10 may also benefit patients with Alzheimer's disease, particularly those in the early stages of the disease. CoQ10 is neuroprotective in cell culture and animal models relevant to AD. Importantly, a closely related quinone called idebenone was reported to be effective in clinical trials in AD patients in Europe and Japan (Bergamasco et al, 1994). Coenzyme Q10 and idebenone both improve energy metabolism and exhibit antioxidant activity, which appears to be the basis for their neuroprotective actions. Of course Co Q10 is available at any health food store, and the findings in the Parkinson's patients will likely stimulate an increase in sales of this supplement.

View all comments by Mark Mattson

Focus on the Mitochondrion in Neurodegenerative Disease
Mitochondrial structure and function decline with age, and especially in age-associated diseases including neurodegeneration. Mitochondrial damage appears to be a primary cause for the development of human AD and AD-like pathology in transgenic mice (Hirai et al., 2001; Aliev, 2002; Castellani RJ et al., 2002; Aliev et al., 2002; 2003a; 2003b). In addition, AD and/or other cerebrovascular pathology is characterized by significant decreases of cytochrome oxidase activity—but not immunoreactivity in different cellular compartments such as large pyramidal neurons (Hirai et al., 2001), vascular endothelium and perivascular astrocytes or pericytes (Aliev et al., 2002; 2003a; 2003b) and it coexists with chronic brain inflammation. Therefore, drug...  Read more

Focus on the Mitochondrion in Neurodegenerative Disease
Mitochondrial structure and function decline with age, and especially in age-associated diseases including neurodegeneration. Mitochondrial damage appears to be a primary cause for the development of human AD and AD-like pathology in transgenic mice (Hirai et al., 2001; Aliev, 2002; Castellani RJ et al., 2002; Aliev et al., 2002; 2003a; 2003b). In addition, AD and/or other cerebrovascular pathology is characterized by significant decreases of cytochrome oxidase activity—but not immunoreactivity in different cellular compartments such as large pyramidal neurons (Hirai et al., 2001), vascular endothelium and perivascular astrocytes or pericytes (Aliev et al., 2002; 2003a; 2003b) and it coexists with chronic brain inflammation. Therefore, drug delivery to mitochondria may be a new opportunity for treatment of aged-associated diseases such as AD.

The study by Saydoff and coworkers demonstrated that oral uridine prodrug PN401 is neuroprotective in mitochondrial and neuroinflammatory models of AD. PN401 is a prodrug that efficiently delivers uridine after oral administration in humans. The pyrimidine uridine forms the backbone of uridine diphosphate sugars that are required for the glycosylation reaction. Therefore pyrimidine derivatives are also critical for phospholipid and glycogen synthesis. De novo biosynthesis of uridine nucleotides is coupled to the respiratory chain via the mitochondrial enzyme dihydroorotate dehydrogenase. Saydoff and coworkers show in a chemical hypoxia model that PN401 significantly decreases weight loss, mortality, and apoptotic cell loss in the cerebral cortex induced by azide infusion (subcutaneous) for two weeks.

The novelty of this study is that it shows for the first time that oral delivery of PN401 can protect mitochondria against hypoxia and suppress neuroinflammation after the infusion of lipopolysaccharides. PN401 significantly attenuated the increase in interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the plasma and brain in response to lipopolysaccharides. This study confirms our recent finding that AD needs to be considered a hypoperfusion-induced mitochondrial disease with neurological consequences (Aliev et al., 2002; 2003a; 2003b). Future research should explore a possible protective effect of PN401 in a transgenic mouse model of AD, especially after chronic hypoxia and/or ischemia/reperfusion. This new research direction may provide AD patients with an alternative treatment option.

References:
Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA. Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. Abstract

Aliev G, Seyidova D, Neal ML, Shi J, Lamb BT, Siedlak SL, Vinters HV, Head E, Perry G, Lamanna JC, Friedland RP, Cotman CW. Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann N Y Acad Sci. 2002 Nov ; 977():45-64. Abstract

Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, Obrenovich ME, Perry G, Smith MA. Role of mitochondrial dysfunction in Alzheimer's disease. J Neurosci Res. 2002 Nov 1;70(3):357-60. Review. Abstract

Aliev, G. Is nongenetic Alzheimer's disease a vascular disorder with neurodegenerative consequences? J. Alzheimer's Disease, 2002, V.4 (6):513-516. (No abstract available)

Aliev G., Seyidova D., Lamb B.T., Obrenovich M., Neal M.L., Siedlak S.L., Vinters H., LaManna J.C., Smith M.A., and Perry G. Vascular Endothelium and Mitochondria as a primary target for the development of human AD and AD-like pathology in transgenic mice. Neurological Res., 2003a (In press)

Aliev G. Seyidova D., Lamb B.T., Raina A.K., Obrenovich M., Siedlak S.L., Vinters H., LaManna J.C., Smith M.A., and Perry G. Vascular Hypoperfusion, Mitochondria Failure and Oxidative Stress in Alzheimer Disease. Proceeding Indian National Science Academy, 2003b (In press).

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This interesting abstract indicates that a prodrug for uridine protects against mitochondrial and inflammatory damage in cultured cells and experimental animals. The result is not surprising, since uridine is known to protect mitochondria against free-radical damage. The Alzheimer brain is under oxidative stress, but the relevance of this approach to treating human Alzheimer’s disease is conjectural.

View all comments by John Blass