Posted comment on ´Pathological tau strains from human brains recapitulate the diversity of tauopathies in non-transgenic mouse brain` by S. Narasimhan, J.L. Guo, L. Changolkar, A. Stieber, J.D. McBride, L.V. Silva, Z. He, B. Zhang, R.J. Gathagan, J.Q. Trojanowski and V.M.Y. Lee and published in Journal of Neuroscience 2017 37 (47) 11406
Narasimhan and colleagues reported in their article the results of their investigation into three different structural conformations of tau aggregation (called tau strains) and their cell-to-cell transmission in non-transgenic mice (non-Tg mice). The tau strains they investigated were all linked to neurodegenerative diseases with known tau pathology eg. Alzheimer disease (AD-tau), supranuclear palsy (PSP-tau) and corticobasal degeneration (CBD-tau). The authors began their article by describing the similarities and differences between these illnesses from a neurochemical point of view.
In their study, Narasimhan and colleagues injected into female non-Tg mice purified tau obtained from the post-mortem grey cortical matter of patients suffering from either Alzheimer disease (AD-tau) or corticobasal degeneration (CBD-tau). In the case of PSP-tau, the injected material was purified matter from the lentiform nucleus (globus pallidus and putamen) of patients who had suffered supranuclear palsy. The authors also set up primary neuron cultures from the hippocampus of CD1 embryonic mice. Investigations carried out were to determine the differences in tau strains relating to potency, the cell type specificity of transmission, brain region development and the timing of tau pathology.
The results obtained showed Narasimhan and colleagues that there were differences in the potency of the three tau strains considered. Using Western blots with anti-tau antibodies, the authors found as expected in AD-tau the 6 isoforms of tau with 3 prominent bands of 3R and 4R tau. Both CBD-tau and PSP-tau demonstrated 2 bands corresponding to the 4R isoform. All isoforms were found to be hyperphosphorylated as expected. The CBD-tau appeared to contain some 3R isoforms and this was attributed to overlapping Alzheimer disease (AD) pathology in the frontal cortex found with this disease. Using an assay with increasing guanidinium chloride (GuHCl) concentration and protease digestion, the authors were able to perform a conformational stability assay on the three tau strains. They found that the Western Blot for PHF-1 used to determine protease resistant bands showed the three strains had different banding patterns without GuHCl. AD-tau had smaller tau fragments (15-20kDa) and CBD-tau and PSP-tau larger (approx. 25kDa). Incubation with GuHCl led to differing PK resistance with CBD-tau being the least stable, AD-tau more stable and PSP the most stable although the two PSP-tau cases used gave different results. Narasimhan and colleagues therefore concluded that there are different strains of tau pathology in the three diseases investigated.
In their second set of experiments, Narasimhan and colleagues seeded non-Tg primary hippocampal neurons with the different tau strains and looked at the subcellular localisation of the tau aggregates. They found that insoluble tau was required in each case and that these corresponded to strains found in humans eg. AD-tau had 3R and 4R isoforms. The AD-tau produced thread-like immunoreactivity in the axons of hippocampal neurons with rare perikaryal inclusions whereas CBD-tau produced frequent perikaryal and axonal inclusions and PSP-tau the most (approx. 300 times the potency of the other two). Again, the PSP-tau showed discrepancy between the two samples by not inducing tau pathology in all cases.
The investigation of in vivo localisation of endogenous tau aggregation required the tau strains to be injected into the hippocampus and overlying neocortex of the non-Tg mice. As a result, Narasimhan and colleagues found over the 3 month experimental period differences in potency between the tau strains. Case 1 of the PSP-tau strain again presented different characteristics in that it was the most potent at propagating tau aggregation. CBD-tau induced less extensive tau pathology and AD-tau the least. Both PSO-tau and CBD seeded tau aggregates in more neuronal subtypes in the hippocampus (eg. dentate granules, hilar neurons and CA3 neurons) whereas AD-tau primarily seeded tau aggregates only in the hilar neurons. The same cell-type specificity was exhibited in non-Tg mice as in humans with AD-tau aggregates observed in neurons and PSP-tau and CBD-tau in neurons, oligodendrocytes (oligodendrocytic inclusions in the white matter tracts such as fimbria and corpus callosum and resembling the oligodendrocytic coiled bodies found in humans) and astrocytes (astrocytic plaques similar to human CBD or in the case of human PSP, tufted astrocytes as well as astrocytic plaques).
In both the PSP-tau and CBD-tau strains neuronal tau aggregates were observed 1 month after seeding. The investigation of the tau pathology in these tau strains showed that injection of human tau led to endogenous mouse tau aggregation in the neurons and glia. An investigation of the tau aggregates formed was carried out using antibodies specific to the tau conformations seen at the different stages of pathology. (The pathology of tau aggregation is believed to follow a pattern with tau becoming first hyperphosphorylated. This is demonstrated by antibodies AT8 or AT180 dependent on the position of the phosphorylation eg. pSer 202/Thr 205 or pThr 231. Then, misfolding and aggregation occurs which is demonstrated by the antibody MC1 for misfolded conformation around the interaction of the N- and C- terminals of tau and TG3 antibody for misfolded conformation around the pTHr231 site. Finally, the tau aggregates form neurofibrillary tangles comprising of beta sheet structures and this is demonstrated by the amyloid-binding dye, ThS). In their experiments, Narasimhan and colleagues found that in the case of AD-tau a small set of the seeded neuronal aggregates were weakly positive for AT180, TG3 and MC1 at 3 months. CBD-tau aggregates instead at this same time period demonstrated strong positive results for AT180, MC1 and TG3 antibodies, but only rare occurrences of binding of the amyloid-binding dye, ThS. However, PSP-tau showed all. Therefore, the authors concluded that the pathology was different for each tau strain. An investigation of the glial effect also supported the differences between the tau pathology of the three tau strains investigated. CBD-tau astrocytic tau aggregates were found to be positive for AT180 and mildly positive for MC1 whereas oligodendrocytic tau inclusions were positive for AT180, MC1 and TG3. None of the tau strains were positive for the amyloid binding dye ThS demonstrating that the final stage of neurofibrillary tangles had not been reached within the one-month time period.
The authors continued with an investigation into the spatiotemporal transmission of the tau strains. The pathology for all 3 strains was found to increase and spread from 1-3 months to other connected CNS regions, but the number of seeded tau aggregates did not increase any more from 6-9 months. The number of PSP-tau aggregates was found to be stable from 3-9 months and the number of AD-tau and CBD-tau aggregates actually decreased. No significant neuron loss was found in AD, CBD and PSP tau over the post-injection time intervals with the PSP-tau strain retaining more tau inclusions than the other two in the ventral hilus at 9 months post-injection. The investigation of transmission showed that all 3 tau strains transmitted tau aggregates to sites connected with the injection sites with the AD-tau strain producing a narrower spatial pattern than the other two (less cortical regions) at 3 months, but more at later stages. All three tau strains demonstrated transmission to the olfactory bulb which was not connected to the injection sites.
An investigation into the spatiotemporal transmission of tau pathology relating to the glial population involved Narasimhan and colleagues seeding glial tau inclusions in non-Tg mice by injecting CBD-tau or PSP-tau. The transmission of tau for both presented similar properties. CBD-tau mice developed more astrocytic tau pathology compared to PSP-tau which had more oligodendrocytic tau inclusions. Both remained stable even at 6-9months. The astrocytic tau pathology in CBD-tau injected mice spread with time from the ipsilateral ventral hippocampus observed at 3 months to the contralateral hippocampus and cortical regions at 6-9months. This was contrary to results observed with neuronal transmission. Mice injected with PSP-tau oligodendrocytic tau aggregates presented with significant transmission from the ipsilateral to contralateral side of the white matter tracts including the fimbria and corpus callosum.
The authors concluded their study by looking at whether the site of initiation and neuronal connectivity of that site determines the distribution and spread of tau aggregates in taupathies rather than being dependent on the tau strain. Therefore, the authors injected AD-tau, CBD-tau and PSP-tau aggregates into the dorsal thalamus of non-Tg mice. Six months later the authors found the same distribution of tau aggregates as described above when the injection sites were the hippocampus/cortex areas. PSP-tau was still the most potent strain and CBD-tau induced glial-tau pathology whereas AD-tau did not. The spatial distributions of the neuronal tau aggregates were similar for all three strains, but the spatial distribution of the tau pathology was different. This supported the authors` hypothesis that the site of initiation determines the distribution and spread of the tau aggregates and is independent of the actual tau strain. In the case of the injection site being the thalamus, the astrocytic tau pathology spread in the same brain regions as the neuronal pathology suggesting that neuronal-to-astrocytic propagation of tau pathology is involved in the spread of astrocytic tau pathology.
The authors ended their article with several conclusions. They began by describing the value of their research (eg. the use of authentic tau strains; the importance of using non-TG mice; the significance of their work being the only study that describes tau transmission) and stated that they had found that tau strains have different folding patterns and hence, have different neurochemical characteristics. The taupathies observed probably reflect these differences and are not likely to be linked to whether 3R or 4R tau isoforms are present. Narasimhan and colleagues` studies also showed that the PSP-tau form was the most potent (300 times more potent than other strains), but it is likely that heterogeneity of PSP-tau strains exist. The tau strains were also found to produce different pathologies in non-Tg mice and these matched results of human studies. PSP-tau was the most potent in vivo propagating more neuronal tau aggregates to anatomically connected areas than the other strains independent of the location of the injection site. This appeared to support the results of clinical syndrome studies. The authors also observed differences in tau pathology relating to the development of tau aggregates between the three tau strains in the non-Tg mice and this gives information about the diversity of human tauopathies. For example, the formation of tau aggregates of PSP-tau and the slightly lower potent CBD-tau relate to the shorter clinical course of both resulting diseases compared to AD where there are likely to be fewer aggregates developing in the earlier stages, but with an accumulation over long periods of time. According to Narasimhan and colleagues all three tau strains appeared to have similar spatial distributions of neuronal pathology independent of the site of injection. This did not support research by others which use artificially derived tau strains and who found that regional differences were observed. The authors also concluded that all tau strains were capable of inducing neuronal tau aggregates in the same brain regions and this was dependent on the site of injection. This observation too was not supported by others who showed that the trans-entorhinal cortex is the earliest site for AD tau pathology, striatum and prefrontal cortex for CBD and the brain stem in PSP. The authors suggested that the different sites of initiation lead to development of unique tau strains and spread to anatomically connected areas. As far as glial tau pathology of CBD-tau and PSP-tau were concerned the authors found converse effects between glial and neuronal tau pathology in selected brain regions. This suggested to them that either the transmission of pathological tau seeds goes from neurons to neighbouring glial cells namely astrocytes or that astrocytic tau pathology spreads from one astrocyte to another through the gap junctions between them. Transmission of oligodendrocytic tau aggregates was suggested to be due to an unknown mechanism spreading from glial cell to glial cell through the white matter tracts. The authors concluded their article by stating that their results aid tau-targetted therapies for those neurodegenerative diseases known to be linked to the aggregation of tau.
What makes this article interesting is that it continues to show the complexity of the brain and how the mechanisms of neurochemical systems and reactions cannot be considered foregone conclusions for all cells and all brain areas. The article commented on in this blog reports the results of three tau strains and their pathology both neuronal and glial. It shows that even though the general tau neurochemical mechanisms may be the same, something about the particular structure of the tau molecules, the cells and even the brain areas cause diversity in the consequences of their actions. Particularly in the consideration of taupathology because of its link to Alzheimer disease (AD) we have bear in mind that what we see in the test-tube, the neuronal cell line, the rodent model may not at the end of the day be directly transferrable to what happens in humans. But we have to start somewhere and in the case of taupathology we have to ask several questions: What does tau do under normal conditions? What causes it to go ´rogue`? What happens under pathological conditions? And whether there is any hope of stopping this and even if we were able to, would neurodegeneration still occur under those conditions, just brought about by other means? We will consider these questions only from the perspective of the brain and cognitive functioning since AD is given as an example of tau strain in the Narasimhan article and the main focus of this blog is this particular organ of the body.
So to begin, we look at tau as the protein it is functioning normally in the brain`s neuronal and glial cells. Tau exists in isoforms the most common of which are the 3R and 4R forms. It is a Microtubule Associated Protein (MAP) meaning that it is membrane bound and associated with the cellular cytoskeleton in both neuronal cells and glial cells. Tau acts as a ´bridge` for microtubules one of the components of the cytoskeleton so that they lie straight and aligned in the intracellular environment. Microtubules with attached molecular motors are part of the cytoskeleton responsible for vesicular transport within the cell and cellular endocytosis and exocytosis. These functions are important in neurons particularly for the nerve signal transmission, the transport of metal ions, neurotransmitters and receptors, but are not necessarily linked to the transport of ions like sodium or potassium involved in neuronal action potentials since these have their own transport systems in the form of pumps and channels. There is an exception, however to this, since calcium ions can be found in intracellular stores and vesicles and are released by exocytotic mechanisms. It should also be noted that tau itself can be found in the extracellular environment since in some cortical cell lines tau has been found free-floating and un-aggregated outside the cell. These tau proteins appear not to be full length as those existing intracellularly, but are present as C-terminal fragments. Research shows that these fragments are released from not only active neuronal cells, but dead and dying ones too. Even though their function has been described as being unknown, we will see later that they can be linked to the spread of tau pathogenicity and so should not be disregarded.
Therefore, ´normal` tau is essential for the required exocytotic and endocytotic mechanisms important for neuronal and glial functioning. As research shows at some point, tau goes ´rogue` meaning that the pathological tau ie. a tau form that can cause neurodegeneration occurs. This pathological tau form appears to be of the 4R isoform type in most cases and this is supported by the work of Narasimhan and colleagues. Although all their examples have this 4R form, not all the studied taupathies demonstrate the same potency indicating that the tau strains have different structural conformations. Since structural conformation is based on different amino acid constituents we have to assume that these pathological tau forms have to a certain degree different amino acids which lead to different binding and different tertiary and quartenary structures.
Therefore, what can cause the normal tau protein to turn ´rogue` and hence, demonstrate different binding and functioning? The initial stage of the pathological process has been found to be the hyperphosphorylation of the tau protein. Hence, one possible cause of naturally producing pathological tau is a mutation of the tau gene leading to ´rogue` isoforms being formed that are prone to being phosphorylated. Two other suggestions have been made. The first is the one that people most commonly favour because of its link with AD and that is the presence of beta amyloid. This is described in more detail later, but one factor is that the presence of beta amyloid induces the hyperphosphorylation of tau proteins by glycogen synthase kinase 3 (GSK3) whose production is promoted by beta amyloid. Beta amyloid can also increase the release of extracellular tau aggregates and tau fragments. These can be taken up subsequently by the synaptically connected neurons and induce further intracellular tau hyperphosphorylation so that the taupathy spreads through the connected cell network. This is a natural process, but Narasimhan and others use the mechanism experimentally to investigate taupathy by seeding neuronal cells whether in vivo or in vitro by injection or exposure to pathological tau and hence, can induce pathological changes in the cellular networks that they can control.
The ´rogue` tau produced has a negative influence on the neuronal and glial cells ending with cell death. Taupathology reflects the working of the brain area which is based on the ´speciality of the cells` present plus the connectivity of the cell and the area to other cells and areas within the brain. Tau pathology can be seen before any symptoms of cognitive deficiency and therefore, provides a mechanism for early diagnosis of neurodegeneration if it can be measured reliably. It begins at the cellular level and as said above is dependent on hyperphosphorylation of the tau proteins which requires the action of a protein kinase (for example the beta amyloid linked glycogen kinase 3). The hyperphosphorylation causes different amino acid binding and different tertiary and quartenary conformational structures that lead to the misfolding and aggregation of the tau proteins. Such changes begin with the axons where neurophil threads appear. Using silver staining preparations researchers have shown that inside a normal cell, one or more single fibres in the axons leading to the soma are prominent through their thickness and silver impregnability. As the pathology advances, then many fibrils are arranged parallel to one another and demonstrate the same changes. They then accumulate forming thick bundles and neurofibrillary tangles are observed in the soma. Taupathology can also occur in glial cells with astrocytes forming plaques or a ´tufted` astrocytic appearance or for oligodendritic cells the characteristic oligodendrocytic coiled bodies. As Narasimhan and colleagues described in their article, the highest level of damage was caused by tau that had the greatest conformational stability and this view is shared by others who describe the severity of AD correlating to the number and distribution of the neurofibrillary tangles. As the tau pathology progresses eventually the nucleus and cytoplasm disappear and only the bundle of tangles of aggregated fibres remain. This type of cell destruction appears to occur by a different mechanism to that of the more common apoptosis and necrosis.
The effect of taupathology on brain functioning and the cognitive symptoms observed depends on the brain area involved and its connectivity to other regions. Unlike other destructive measures like injury or stroke, tau pathology appears under natural conditions to spread and in the case of AD, this spread seems to be of a particular pattern. AD is said to begin with the region of the perirhinal cortex (which receives input from the parietal cortex and visual cortex) and spreads to the entorhinal cortex and then to the hippocampal areas of the dentate gyrus (DG) then CA1 and CA3. The fornix, which is the area receiving the major output from the hippocampus, also appears to be susceptible. Narasimhan and colleagues also reported such a spread in the case of their induced taupathies and also noted that in each taustrain the olfactory lobe was affected.
Therefore, with such devastating effects at the cellular level and with its capability of spreading to adjacent brain areas, we have to ask whether there is any hope to stopping taupathology once it has begun? Does the cell itself try to overcome tau phosphorylation or misfolding for example by gene expression changes as a reaction to pH changes or the increased action of protein kinases responsible for the initial phosphorylation? Or would increasing the production of new, unadulterated tau or even inducing higher production of new cells in the case of the hippocampus which is known to exhibit neurogenesis in response to neuronal activation. It appears not and also the natural response to neuroinflammation seems not to be functioning normally. In AD there is an observed increase in stress markers. Savage and coworkers found that there was a robust inflammatory response caused by the accumulation and subsequent deposits of beta amyloid in the brain. This inflammation leads to cognitive deficits as also observed with injury and stroke for example andmarkers for activated microglia show increased neuroinflammation consistent with the spread of AD. Under normal conditions, the microglia perform immune-like actions and migrate to and put out processes within the beta-amyloid plaques as they would with any other cell ´invader`. However, they are unable to efficiently perform phagocytosis and cannot clear the presenting plaques. Therefore, the local neuroinflammation response is abnormal in taupathies and this supports the success of anti-inflammatories to decrease the AD effect. For example the anti-inflammatory etanercept leads to an improvement after 3 months and is believed to work through action on tumour necrosis factor alpha (TNF – alpha) which binds with beta amyloid.
Although it appears unlikely that there is any natural mechanism to prevent taupathology from causing cell destruction and spreading to other cells, in the case of AD, plasticity of the brain cells and redundancy in the neuronal cell system is likely to ´protect` the individual from the highly negative effects on cognition until about 80% of degeneration has occurred and this probably occurs in other taupathies as well. From the perspective of administration of medicines, the use of anti-inflammatories appears to have some success in limiting taupathology as described above. Methods involving the reduction of pathological tau by enforcing its removal also appear to have some success since research has shown that immunotherapy using specific antibodies against tau oligomers will lead to their removal and reverse memory deficits in Tg2576 mice. However, we have to ask even if we stop taupathology, would it stop neurodegeneration being caused by other means? Is pathological tau then the limiting factor in this type of neurodegeneration or it is just one factor of a number that have the same results? This question has to be answered because of the relationship which we have already indicated between tau and amyloid. For example as described above beta amyloid causes oxidative stress of the cell and increased quantities of all forms of extracellular tau and in the case of AD, changes in amyloid appear to be the initial stage of the disease.
The amyloid precursor protein (APP) like tau is a membrane-based protein. It is a highly conserved protein expressed in many tissues and concentrated in neuronal synapses. Amyloid is an intergral part of the cell membrane and has an important role, like tau, in the endocytotic mechanism with its interaction with the molecular motor, kinesin and therefore, is part of the cell signalling, LTP and cell adhesion mechanisms. It is also important according to some researchers for iron transport in the neuronal cell. The APP either possesses ferroxodise activity facilitating iron export from the cell through its interaction with ferroportin, an activity blocked by zinc which is accumulated by beta-amyloid presence as in AD, or by APP acting to stabilise ferroportin in the plasma membrane. APP is also reported to be linked with intracellular copper where APP expression decreases brain copper levels, but increasing copper levels decreases beta amyloid and APP (Maynard et al.)
The pathological form of amyloid is said to be the beta form (beta amyloid) which is formed by splitting the amyloid molecule by 2 membrane based enzymes, beta-secretase and gamma-secretase. The splitting process occurs twice so that the resulting beta amyloid is released and forms a layer on the outer membrane. Beta amyloid therefore is a 37 – 49 amino acid based protein which has a beta-pleat conformational structure consisting of 2 or more beta strands connected by hydrogen bonds. Although it is known to be the pathological form in taupathies, beta amyloid contributes also to normal brain functioning and it is possible that it is an imbalance of this that causes the pathology. Under normal conditions, beta amyloid aids recovery of brain cells by binding to toxic agents such as metal ions and excessive amounts of brain neurotransmitters both of which can cause abnormal neuronal firing. Like APP, there is again a link to metal homeostasis with iron and copper. Wan et al. observed that beta amyloid increased the levels of intracellular iron in a certain cell line that over-expressed the APP protein. This was linked to an increase in the expression of the iron transporter, but not transferrin. In the case of copper, Maynard et al. found that like APP, beta amyloid expression leads to decreased brain copper whereas increased brain copper leads to decreased levels of beta amyloid and amyloid plaque formation. In the case of removal of toxic agents, the beta-amyloid pleats clump the negative agents to form plaques so they are easier to remove from the cell. It is said that this ´mopping up` turns amyloid into a powerful enzyme that forms hydrogen peroxide which itself can kill the neuronal cell in a reactive oxidative stress reaction. It is believed that instead of this clumped beta amyloid form it is instead soluble beta amyloid that is the problem in the initial stages of AD (Selkoc and colleagues) since there is greater link between this and dementia. However, the formation of plaques plays a role in AD where too much beta amyloid is produced. This has been reported to occur via several mechanisms eg. through high activity of gamma-secretase, incorrect timing of amyloid splitting, or a mutation of gamma-secretase so that the amyloid molecule is split in the wrong place forming the ´toxic` form of beta amyloid.
The logical inference is that because beta amyloid accumulates excessively in AD, its precursor protein APP would be elevated as well. However, it was found that neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques. This finding indicated that this deficit in APP results from a decline in production rather than an increase in catalysis and it is this loss of a neuron’s APP that has been said to affect the physiological deficits that contribute to dementia. We must balance this however with the observations that treatment with beta amyloid leads to a 5 times higher number of hyperactive brain cells and worsens AD symptoms as well as having the detrimental effect on the formation of pathological tau.
Therefore, in answer to the question that if we stop taupathology would we prevent neurodegeneration by other means it looks unlikely since beta amyloid would be likely to form that would also lead to detrimental affects on endocytosis and result eventually in cell death. Several methods have been suggested to reduce beta amyloid and these have been linked to slower AD progression, but like tau these too are not natural. For example, small-molecule inhibitors of the beta-secretase enzyme (eg. BACE1, JKL inhibitor) have been found to lower beta amyloid levels and reverse deficits in conditioning memory deficits. These are also associated with increased microglial functioning, hence increasing the neuroinflammation response. Inhibitors of insulin –like growth factor receptors have also been found to improve spatial memory and reduce anxiety in a knocked-out-neuronal IGF-1R APP/PS1 mice model. Fewer amyloid plaques and lower levels of beta-amyloid were observed. Less traditional methods have also been found to have some success such as the drug, aducanumab which has been found to decrease AD progression and the deposition of beta amyloid. A compound from grape skins, resveratrol, has also been found to lead to decreased levels of beta amyloid in the blood as well as ultrasound which has been used in mice and shown to cause the breakdown of plaque formation.
However, even if we are able to stop toxic beta amyloid production and plaque formation, we still have not eradicated the other factor observed in AD and taupathology and that is the hyperexcitability of the neuronal firing observed in the affected areas initially afflicted. Hyperexcitability is linked to a number of different factors. There is reported acetylcholine dysfunction in the areas of the EC, forebrain (could be parietal and visual areas) and PFC as a result of for example excessive acetylcholine, the depletion of K+ channels in the dendritic hippocampus (a decrease in potassium pumped out of cell occurs resulting in continual firing) and increased SK channel inductance. A continuation of LTP excitation instead of the switch to inhibitory LTD has also been reported in the case of the hippocampus which is the area badly affected in AD and linked to the cognitive deficits seen. In AD itself, the observed presence of beta amyloid leads to a number of neuronal cell changes that cause hyperexcitability such as increased calcium ion entry, increased glutamate release and decreased uptake and overactive mGlu5 receptor activity. Even if it were possible to remove excess acetylcholine or glutamate, tau or amyloid pathology may not be preventable since noradrenaline dysfunctioning has also been observed in the region locus coereleus in AD so the situation may be even more complicated than previously thought with multiple neurotransmitters being affected.
And so this is where we are. It would be nice to put AD in a box labelled ´caused by pathological tau or caused by pathological beta amyloid` but as this brief comment shows the subject is immensely complex with multiple players with both positive and consequential negative effects. Success in solving this problem will come to those that can look at it from multiple angles not only at the cellular level, but also at the level of brain area connectivity and for this to happen the interrelationships of thousands and thousands of factors have to be discovered, their boundaries investigated and then considered not singly but as part of a functioning whole.
Since we`re talking about the topic……
……can we assume that if AD-tau is seeded using the non-Tg mouse we will be able to see the same reduction in theta brain wave synchronisation between the hippocampus and prefrontal cortex during a spatial memory task as that using a knock-out APP mouse? Would exposing the mouse on a regular basis to a light flickering at 40HZ as given by Boyden and team`s experiments protect the mouse from the AD-tau pathology and restore the theta brain area synchronisation and memory performance?
……..the administration of clioquinol is said to lead to reduced abnormal beta-amyloid synaptic targeting and a reduced level of ZnT3 which also reduces abnormal beta-amyloid levels and plaque formation. This implies a link between intracellular zinc ion levels and Alzheimer disease but there have been disputes about whether a rise in zinc ions actually occurs. Would seeding with AD-tau and measuring intracellular and extracellular zinc levels in the hippocampus and the prefrontal cortex clarify the situation particularly if the levels of ions were measured over the course of the development of the pathology?
….a mutation at site A6737 in the APP gene is said to protect against the development of Alzheimer disease pathology. Can we assume that if we investigate how this mutation translates into alteration of amino acid content and hence, tertiary and quartenary APP molecular conformation we may be able to induce on a local scale the same amino acid alteration by using enzymes or more long-term by specific DNA manipulation?