Posted comment on ´Iron Level and Myelin Content in the Ventral Striatum Predict Memory Performance in the Aging Brain` by T.K. Steiger, N. Weiskopf, and N. Bunzeck published in The Journal of Neuroscience, 23rd March 2016, 36(12): p.3552
Steiger, Weiskopf and Bunzeck`s paper looks at the relationship between iron accumulation, the degeneration of neuronal myelin sheaths and brain memory performance in the elderly. They examined the performance at the verbal learning memory test (VLMT) against the degree of myelination and iron accumulation for a group of 17 participants aged 18-32 against a group of 31 participants aged 55-79. Grey matter volume was also measured using voxel-based morphometry (VBM) and MT maps were segmented into grey matter (GM), white matter (WM) and CSF. To test for differences in R2* and MT parameters, a voxel-based quantification (VBQ) analysis was used and statistical analysis was applied to all results. Brain memory performance was measured using VLMT where a list of 15 non-related items (List A) was learnt and immediately recalled five times to give the parameter ´VLMT total learning`. This process was repeated using an alternative word list (List B) which was immediately recalled once. The participants were then asked to recall List A and then again after a delay of 30 mins. The difference between the first and second recall session was designated ´VLMT consolidation`. Cued recall was then performed using words taken from both List A and List B plus additional similar words. Participants were required to identify components of List A and these items were termed ´VLMT recognition`. Regression analyses were performed on the relationship between GM, MT, R2* maps and VLMT performance.
Steiger, Weiskopf and Bunzeck found in their investigation that there was a decrease in grey matter volume in the elderly brain relative to the young. Bilateral decreases were observed in the putamen, orbitofrontal cortex (OFC), precentral and postcentral gyri, supplementary motor area, left supramarginal gyrus, right occipital cortex, right superior temporal gyrus, the right medial frontal gyrus and right inferior parietal gyrus. A decrease in myelin was also observed in the elderly relative to the young as shown by VBQ on MT maps and this was registered for areas within the left hippocampus, right thalamus, caudate, cerebellum, post central and precentral gyri, right colliculi superior, left occipital cortex, and widespread WM tracts.
The authors also found using VBQ on R2* maps an increase in iron levels in the elderly brains and this was observed within widespread brain regions including the basal ganglia, bilaterally in the putamen, pallidum, caudate, ventral striatum, and partly within the occipital cortex. A further investigation of the basal ganglia of elderly participants using the mean R2* and MT found negative correlation between myelin and iron in the area of the ventral striatum in the elderly. However, direct comparison between both correlations for elderly and young participants did not give a significant result and this was explained by the authors as possibly due to the small sample size.
Both markers of iron and myelin (and the ratio) were found by the authors to predict VLMT performance for the elderly participants. The VLMT scores of the elderly were used as covariates in whole brain linear regression models on GM, R2* and MT maps. The authors found within the ventral striatum a positive correlation between VLMT and MT, but negative VLMT and R2*. The VLMT performance predicted by the ratio MT/R2* in the ventral striatum showed increased iron levels in the elderly participants. Steiger, Weiskopf and Bunzeck also reported significant effects within the vicinity of the corpus callosum with learning correlating to MT white and grey matter. However, whole brain regression analysis on grey matter volume and VLMT scores was found not to be significant.
From their results the authors of this paper concluded that there are age related decreases in grey matter volume and this finding was supported by reports from other researchers who stated that the grey matter volume decrease is due to loss of neurons, changes in synaptic density and /or axonal or dendritic arborization. Steiger, Weiskopf and Bunzeck concluded that decreases in myelin in the elderly as seen in lower levels of white matter tracts and in subcortical regions indicates less macromolecular content (mainly myelin) and probably demonstrates demyelination and dysfunctional re-myelination in the aging brain. This provides an understandable link to VLMT performance since myelin is a factor in the speed of neuronal signal conduction and interconnectivity between brain areas important for learning. Also, learning induces myelination linked to oligodendrocytic function, which has been found to decrease with age. The decreased myelin level could also be due to damaged oligodendrocytes releasing iron into the surroundings. The authors found increased iron in the elderly brain mainly in the basal ganglia, a reason for which, although unclear, was suggested by some that it is triggered by an attempt by the cell to maintain a declining system through increasing metabolic processes. The rise in iron accumulation was found to be region specific and ventral striatum iron accumulation was found to be linked to demyelination and impairments in declarative memory in the elderly. The authors explained this by citing the role of the ventral striatum in encoding novel information into long-term memory. Therefore, any change in myelin brings about a change in the hippocampal learning mechanism. On investigation of the whole brain, iron and myelin within the basal ganglia was found to account for individual VLMT performance and not the grey matter volume.
In order to provide an explanation for the link between iron accumulation, Steiger, Weiskopf and Bunzeck discussed an association between iron levels and the neurotransmitter, dopamine. In the healthy brain there is a homeostatic balance between dopamine and iron, but this does not exist when the iron levels are high. Therefore, the negative correlation observed in the ventral striatum in these experiments was suggested as indicating that decreased dopamine levels led to decreased memory performance. This hypothesis was supported by experiments involving iron chelation which was shown to reverse any memory impairments.
Therefore, Steiger, Weiskopf and Bunzeck demonstrated in their paper that iron accumulation and myelin reduction seen in elderly brains can lead to observed cognitive impairments measured by the verbal memory learning test.
This article is interesting because it tenuously links a dietary mineral, iron, which should be part of our normal nutritional intake to neurodegenerative disease. It appears that iron accumulates in the brain naturally with age, but can also occur in some neurodegenerative diseases, which are linked with impaired memory and other cognitive skills. Hence, if this tenuous link is correct then there must be a link between iron and the physiology and mechanisms associated with brain memory. Therefore, the question has to be asked where does the mineral iron fit in with the brain memory hypotheses for neurotransmission and cognition? Immediately, obvious connections with brain neuronal efficiency come to mind, for example: the role of iron in myelin production and oligodendrocytes functioning with myelin giving the neurons signal transmission protection; the role of iron in the synthesis of cholesterol, hence affording the neuronal cells with membrane fluidity essential in efficient and correct neuronal functioning; the role of iron in the synthesis of the neurotransmitters, hence providing the instigators of the firing from cell to cell. And it does not stop there because there are less obvious roles of iron in the normal ´housekeeping` carried out in living cells such as energy metabolism (eg. respiratory chain, citric acid cycle associations) and biosynthesis of amino acids and nucleotides for example.
The wide range of roles played by the mineral iron is indicative of its chemical ´flexibility` which gives it biochemical advantages. It allows energy state changes of the molecules in which it is a part due to its inherent capability of being in either an oxidized, or reduced state. Electron transfer whether donation or acceptance can lead to structural conformational changes of the molecules that include the iron ion in their structure and these changes in conformation can be part of the functioning mechanisms of that particular molecule. Heme groups and iron-sulphur clusters are good examples of this. Owing to this electron transfer capability, it is not good for a cell to have iron ions free in the cytoplasm and hence, iron is ´wrapped up` in the form of ferritin (storage), transferrin (serum) and transferrin receptor (entry to cells). The balance of these forms is important and this has been shown with reports of reactive oxygen species (ROS) production and modification of lipids, proteins, carbohydrates, DNA etc. when the balance is disturbed.
Therefore, it is clear that a system relying on signaling transfer such as that found in neurotransmission can be influenced by iron concentrations and this is supported by evidence that memory and cognitive skills can be affected by iron availability. Free iron accumulation has been reported in neurodegenerative diseases such as Alzheimer`s disease. Iron chelation has been found to lead to decreased symptoms, increased memory and inhibited beta-amyloid accumulation, a major contributor to Alzheimer pathology and symptoms. Therefore, is iron accumulation a cause or consequence of Alzheimer`s disease? This is important because if it is a cause then therapy based on modulating iron availability could lead to a reduction in occurrences of the disease.
A look at where iron fits in with the neurotransmission mechanism shows that iron probably plays a role (in addition to those described above) with the beta-amyloid led endocytosis of neurotransmitters into the lysosomal vesicles which forms part of the neuronal cell regeneration after the action potential phase. Disruption of this endocytotic phase by the effects of the dysfunctional amyloid-precursor-protein/beta-amyloid in sufferers of Alzheimer`s disease could explain the observed iron effects. In the hypothetical version of neurotransmission advocated by the author of this blog, ferroportin (the iron transporter for efflux) is attached to the amyloid precursor protein (APP) found in the lipid raft of the presynaptic membrane. PICALM, AP2 and clathrin are all in close proximity. (Other APPs also exist in the neuronal membrane, but are outside the lipid raft and linked to the potassium channel). In normal functioning APP is cleaved by beta-secretase and y-secretase to produce beta-amyloid that is capable of normal conformational changes, and neurotransmitter and metal ion binding. This, hypothetically, leads to the endocytosis of excess neurotransmitter not bound to the post-synaptic membrane by the beta-amyloid aggregate forming vesicular structures from the lipid raft area and transferred within the presynaptic body from cell membrane to endoplasmic reticulum via microtubules and dynein action. The neurotransmitters and membrane components undergo appropriate lysosomal degradation during the transport process and the vesicles are recycled back to the membrane for the next signaling phase. Under normal conditions the conversion of the membrane bound APP to beta-amyloid causes the ferroportin channel to open and reduced iron floods from the cell to be picked up by the oligodendrocytes in the synaptic cleft. This is then used for myelin production, an important mechanism especially in the case of the hippocampus with its high levels of neurogenesis that occurs there during memory formation.
In Alzheimer`s disease it is possible that the unusual cleavage of the membrane bound APP and the formation of the excess beta-amyloid does not produce the membrane conformational changes that leads to the opening of the ferroportin iron transporter resulting in the accumulation of free iron in the cell. Such an accumulation can cause ROS production which is reported in Alzheimer`s disease. Therefore, iron ions are part of the dysfunctions observed at the neuronal level that eventually end in cell death and the peculiar pattern of pathology observed in Alzheimer`s disease. It is also possible that reduced iron ions themselves bind to the abnormal beta amyloid sat on the presynaptic membrane and is part of the dysfunctional endocytotic vesicle formed at the membrane surface. This is supported by the observation that presynaptic iron induces aggregates of inert alpha synuclein and beta-amyloid to form toxic aggregates. Therefore, it is clear that in this case iron is not the cause of Alzheimer`s disease, but a consequence if this hypothesis of neuronal functioning is correct. The limiting factor of the disease appears to be associated more with the formation of excess beta amyloid and dysfunctional APP cleavage.
Iron, however, is not the only metal ion with a role in neurotransmission. Zinc is also an essential mineral that has important biochemical links to efficient neuronal function particularly in the hippocampus where deficiency is associated with causing lethargy and cognitive difficulty for example. A rise in zinc level has been found in Alzheimer sufferers and it is a known blocker of ferroportin, the iron transporting protein whose role in neurotransmission is described above. It is also known that vesicular release and the zinc transporter (Zn-T3) are required for beta amyloid targeting. Therefore, like iron, could zinc be a cause or consequence of the Alzheimer disease?
Zinc is a constituent of many enzymes and in particular the metalloproteases and plays an important role in vesicles and in autophagy (the neuronal endocytosis described before with the breakdown of the neurotransmitters and membranes to be recycled for future synaptic activity). With zinc, the link to neurotransmission is with calcium ions and calcium ion influx which is observed with neuronal excitation. In Alzheimer`s disease, hyperexcitation in the hippocampus leads to massive calcium influx and excess glutamate release. The increase in zinc leads to increased zinc in the lysosomes resulting in membrane disintegration, release of cathepsins and other lysosomal enzymes and increased caspase induced apoptosis. This brings about the neuronal pathology observed in the disease. Again like iron, although zinc deficiency leads to cognitive effects it appears it is not the limiting factor in the causation of Alzheimer`s disease, but a consequence. In this case, hyperexcitation of the neuronal system in this neurodegenerative disease appears to precede the zinc effects.
Therefore, what can we conclude about the role of metal ions in neuronal transmission? We can see that both iron and zinc play a number of specific roles in neuronal signaling and neuronal cell functioning and deficiency can cause abnormal physiological effects that influence the overall functioning of the cell. It is also clear that the causes and physiology of Alzheimer`s disease are complicated with effects observed in the multiple systems, enzymes etc that make up neurotransmission and cognitive functioning, eg. relating to action potential, neurotransmitter synthesis and release, exocytosis and endocytosis, receptor trafficking just to name just a few. Therefore, the likelihood is low that positive changes in the neurotransmission of elderly people with something as simple as iron or zinc administration can cancel out the negative changes seen with Alzheimer pathology leading to retention and improvement of cognitive skills. However, this does not mean that there is not a link between iron and zinc deficiency in the very early stages of Alzheimer`s disease, ie. before the distinctive beta-amyloid accumulation and oligomer pathology is observed. Since the pre-Alzheimer stage develops over many years, who knows what the real instigators are and wouldn`t it be nice if the solution was as easy as administration of zinc or iron! More research is obviously required, but until then maybe everyone should make sure that their daily mineral intake is sufficient.
Since we`re talking about the topic……………………………..
…..are mouse models of Alzheimer`s disease the best models when dietary considerations are being investigated and should it not be that ´elderly` mice are preferentially used for testing for this particular neurodegenerative disease?
……is it that in iron deficient mice, myelin production in the hippocampus is reduced and this can be linked to synchronization problems between this area and others relating to spatial memory and conditioning. In this case, would neuroimaging experiments and brain wave monitoring show the defective connectivity between the hippocampus and other areas linked to memory for example?