Difficulties in iron-sulfur cluster formation can lead to iron accumulation in mitochondria

In Friedreich ataxia iron-sulfur clusters are not formed, due to deficiencies in frataxin which results in iron accumulation in mitochondria. The relevant point is that problems in iron-sulfur cluster formation can be associated with iron accumulation in mitochondria and iron toxicity. The point I have been making is that there are difficulties in synthesizing iron-sulfur clusters in many neurological illnesses due to dysregulation of the transsulfuration pathway which synthesizes L-cysteine. L-cysteine supplies sulfur for iron-sulfur cluster formation.

Iron chelators are now being investigated as treatments for Alzheimer’s disease and Parkinson’s disease. If iron is being accumulated in cells in Alzheimer’s disease and Parkinson’s disease due to difficulties in iron-sulfur cluster formation then iron chelators would not be appropriate treatments. Iron-sulfur cluster formation is increased by supplemental iron. Iron chelators by decreasing iron would decrease iron–sulfur cluster formation leading to iron accumulation in mitochondria and iron toxicity.

Cholesterol, taurine and Alzheimer’s disease

In Alzheimer’s disease there are high levels of homocysteine which points to the transsulfuration pathway (homocysteine to L-cysteine) being dysregulated in Alzheimer’s disease. Taurine is synthesized from L-cysteine. Taurine lowers LDL cholesterol levels. High LDL cholesterol levels, which increase the risk of Alzheimer’s disease, could be connected to the dysregulation of transsulfuration pathway as with dysregulation of the transsulfuration pathway there will be low levels of taurine which will increase cholesterol levels.

Iron and Alzheimer’s disease

Iron overload in various regions of the brain has been postulated to be involved in the pathological mechanism of Alzheimer’s disease. Iron overload in the brain may very well be involved in the etiology of Alzheimer’s disease but iron overload in the brain in Alzheimer’s disease would not be due to too much iron in the diet.

A meta-analysis indicates that serum iron levels are significantly lower in Alzheimer’s disease patients than in healthy controls. Another meta-analysis also indicates that serum iron is significantly lower in patients with Alzheimer’s disease than in healthy controls.

Loss of control over iron metabolism rather that just ‘too much iron’ could be why iron can have negative effects in Alzheimer’s disease. Treatment in AD would demand that control be regained over iron metabolism. Iron chelators have been proposed as a treatment for Alzheimer’s disease. Iron chelators, however, would not be useful in terms of regaining control over iron metabolism. Iron chelators could have negative effects in AD.

The APOE4 allele is associated with lower levels of selenium in the brain.

Bárbara R Cardoso  1   2 Dominic J Hare  1   3 Monica Lind  1 Catriona A McLean  1   4 Irene Volitakis  1 Simon M Laws  5   6 Colin L Masters  1   6 Ashley I Bush  1   6 Blaine R Roberts  1   6 Affiliations

Abstract

The antioxidant activity of selenium, which is mainly conferred by its incorporation into dedicated selenoproteins, has been suggested as a possible neuroprotective approach for mitigating neuronal loss in Alzheimer’s disease. However, there is inconsistent information with respect to selenium levels in the Alzheimer’s disease brain. We examined the concentration and cellular compartmentalization of selenium in the temporal cortex of Alzheimer’s disease and control brain tissue. We found that Alzheimer’s disease was associated with decreased selenium concentration in both soluble (i.e., cytosolic) and insoluble (i.e., plaques and tangles) fractions of brain homogenates. The presence of the APOE ε4 allele correlated with lower total selenium levels in the temporal cortex and a higher concentration of soluble selenium. Additionally, we found that age significantly contributed to lower selenium concentrations in the peripheral membrane-bound and vesicular fractions. Our findings suggest a relevant interaction between APOE ε4 and selenium delivery into brain, and show changes in cellular selenium distribution in the Alzheimer’s disease brain.

DHA and Alzheimer’s disease

Docosahexaenoic acid (DHA) levels are low in Alzheimer’s disease. DHA is synthesized from alpha-linoelic acid which is an essential fatty acid which must be obtained from the diet. For DHA to be synthesized from alpha-linoelic acid, alpha linoleic acid must first be absorbed.

A meta-analysis indicates that homocysteine levels are significantly high in Alzheimer’s disease. High homocysteine levels in Alzheimer’s disease indicate the transsulfuration pathway is dysregulated in Alzheimer’s disease as homocysteine is not being metabolized to L-cysteine which is what the transsulfuration pathway does.

With low levels of L-cysteine there will be low levels of taurine. Taurine is synthesized from L-cysteine. Taurine is needed for the formation of bile acids which are needed for fat absorption. With alpha-linoelic acid not absorbed in Alzheimer’s disease due to low levels of taurine synthesis of DHA will be impaired in Alzheimer’s disease which is what is seen is Alzheimer’s disease. Effectiveness of supplementation with DHA in Alzheimer’s disease could be limited due to a failure to absorb DHA due to low levels of taurine in Alzheimer’s disease.

Taurine only poorly crosses the blood-brain barrier. However, to assist with essential fatty acid absorption taurine does not have to cross the blood-barrier. Taurine by enhancing fat absorption can enhance brain function.

Homotaurine has has been shown to be a promising therapy for Alzheimer’s disease. In Alzheimer’s disease taurine could be taken with with linoelic acid and/or alpha linoelic acid.

There is lots of controversy as to what fatty acid abnormalities are present in Alzheimer’s disease. An important point about essential fatty acid supplements is that without supplemental taurine supplementing with essential fatty acids results in brain fog.

Inflammation, alpha-linoleic acid and taurine in schizophrenia, Parkinson’s disease and Alzheimer’s disease

Inflammation is associated with schizophrenia, Parkinson’s disease and Alzheimer’s disease. A point I have strongly stressed is that the transsulfuration pathway is dysregulated in many neurological illnesses. With the transsulfuration pathway dysregulated there will de decreased levels of L-cysteine which is synthesized via the transsulfuration pathway. Decreased levels of l-cysteine will lead to decreased levels of taurine. Taurine is synthesized from L-cysteine. The bile acid, taurocholate, is synthesized from taurine. With low levels of taurocholate fatty acids will not be absorbed sufficiently. Alpha–linoleic acid is an essential fatty acid that must be obtained from diets. Diets high in alpha-linoleic acid are protective against inflammation. With low levels of taurocholate sufficient alpha-linoleic acid will not be absorbed which will lead to inflammation. . Inflammation in schizophrenia, Parkinson’s disease and Alsheimer’s disease could be due to low levels of taurine which leads to failures to absorb sufficient alpha-linoleic acid which is protective against inflammation.

The association of APOE-ε4 with Alzheimer’s disease could be due to a connection of APOE-ε4 with selenium transport into cells.

Carriers of of the apoE ε4 allele have significantly lower selenium levels in nails and brains. Selenoprotein P is a selenium transport protein. Apolipoprotein E receptor 2 by binding to selenoprotein P regulates uptake of selenium into cells. Both apolipoprotein E receptor 2 and apolipoprotein E regulate transport of selenoprotein P into cells. Selenoprotein P provides protection from amyloid β (Aβ), the main component of amyloid plaques seen in Alzheimer’s disease. The association of apoE ε4 with Alzheimer’s disease could be due to apoE ε4 not being as effective in regulation of selenium transport into cells via apolipoprotein E receptor 2 as other alleles of apoE.

Pantothenic acid and acetylcholine in Alzheimer’s disease

Synthesis of acetylcholine requires acetyl-coenzyme A which donates an acetyl group to choline. With dysregulation of the transsulfuration pathway in Alzheimer’s disease, marked by high levels of homocysteine,  L-cysteine is not synthesized at sufficient levels. See my paper A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway. With low levels of l-cysteine coenzyme A, which is synthesized from pantothenic acid and which requires l-cysteine for synthesis, is not synthesized at appropriate levels. With low levels of coenzyme A the E2 subunit of the pyruvate dehydrogenase complex is underactive. Acetyl-coenzyme A required for the synthesis of acetylcholine is derived from the pyruvate dehydrogenase complex. Dysregulation of the pyruvate dehydrogenase complex could lead to shortages of acetylcholine in Alzheimer’s disease. Shortages of acetylcholine are a hallmark of Alzheimer’s disease. Supplementation with pantothenic acid and sulbutiamine, a fat-soluble thiamine derivative, could improve symptoms of Alzheimer’s disease due to acetylcholine deficiencies such as poor  memory.  There is a lot askew in Alzheimer’s disease so supplementation with  pantothenic acid and sulbutiamine would only be partly effective in Alzheimer’s disease. As always various supplements must be avoided. See the Treatment page on what supplements to avoid.

Measures to improve TCA cycle metabolism might benefit AD patients

Ann Neurol. 2005 May;57(5):695-703.
Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE.

Abstract

Reductions in cerebral metabolism sufficient to impair cognition in normal individuals also occur in Alzheimer’s disease (AD). The degree of clinical disability in AD correlates closely to the magnitude of the reduction in brain metabolism. Therefore, we tested whether impairments in tricarboxylic acid (TCA) cycle enzymes of mitochondria correlate with disability. Brains were from patients with autopsy-confirmed AD and clinical dementia ratings (CDRs) before death. Significant (p < 0.01) decreases occurred in the activities of the pyruvate dehydrogenase complex (-41%), isocitrate dehydrogenase (-27%), and the alpha-ketoglutarate dehydrogenase complex (-57%). Activities of succinate dehydrogenase (complex II) (+44%) and malate dehydrogenase (+54%) were increased (p < 0.01). Activities of the other four TCA cycle enzymes were unchanged. All of the changes in TCA cycle activities correlated with the clinical state (p < 0.01), suggesting a coordinated mitochondrial alteration. The highest correlation was with pyruvate dehydrogenase complex (r = 0.77, r2= 0.59). Measures to improve TCA cycle metabolism might benefit AD patients.

Bill Gates is looking for new ideas on the etiology of Alzheimer’s disease. A heightened focus on the citric acid cycle in Alzheimer’s disease is a new approach to the etiology of Alzheimer’s disease for which there is experimental backing.