neuronal firing dementia model

Posted comment on ´Propogation of tau pathology in a model of early Alzheimer`s disease` by A. de Calignon, M. Polydoro, M. Suarez-Calvet, C. William, D. H. Adamowicz, K.J. Kopeikina, R. Pitstick, N. Sahara, K.H. Ashe, G.A. Carlson, T.L. Spires-Jones, and B. Hyman published in Neuron February 23rd 2012, 73(4) 685, doi:10.1016 j.neuron.2011.11.033

De Calignon and colleagues used the rTgTauEC transgenic mouse model to investigate tau pathology observed in early Alzheimer`s disease. They used the mutant form of human tau P301 in their model with P301 expression linked to the observation of neurofibrillary tangles in frontotemporal depression and selectively expressed in medial entorhinal cortical EC-II cells. Expression of the human tau variant was linked to tet transactivator transgene expression under the control of the neuropsin gene promoter. The entorhinal cortex area was chosen because it receives important input from associative areas of the cortex and provides highly specific output to the dentate gyrus of the hippocampus.
Initially, the transgenic mouse model showed that overexpression of human tau P301L was restricted to EC-II transgene-expressing cells. They found high expression from 3 months in medial entorhinal cortex (MEC) neurons predominately in layer II and the pre- and para-subiculum, especially the latter. Immunohistochemistry using the 5A6 antibody which recognizes the tau epitope between amino acids 19 and 46 found that the mutant tau protein was not only in the MEC layers and para-subiculum, but was also in the molecular layer of the hippocampal dentate gyrus although there was no human tau protein expression at that time. Hence, the authors concluded that tau pathology had progressed to other neurons without relevant gene expression. They hypothesized that the human tau variant (tau itself, a particular species of tau such as hyperphosphorylated tau, misfolded tau, or a tau fragment) might have been released at the synapse, might have entered the neighbouring cells (whether with direct contact, or over the extracellular space) and with no transgene expression, transmitted a misfolded state which recruits the endogenous mouse tau to misfold and aggregate into the observed neurofibrillary tangles. De Calignon and colleagues describe the action of tau in this way as being prion-like. The result was that normal cellular tau distribution is lost and the misfolding and aggregation was observed as beginning in the synapse, leading to the axon (at 3months), soma and dendrites (at 6 months). The systematic tau pathology mirrored neuronal degeneration.
The authors found that the systematic synaptic density loss associated with the initial seeding of the EC-II neurons with human tau variant matched the disease progression. This was consistent with the relationship between neuronal pathway functioning and cognition since it is known that the entorhinal cortex not only gives input to the dentate gyrus in the hippocampus, but also hippocampal CA1 fields and the anterior cingulate cortex. This perforant pathway is linked to memory and cognition and hence developing pathology matched disease symptoms. The tau aggregates found in CA1/CA3 hippocampal areas at 21 months were also without expression of the human tau variant gene indicating that the spread of the tau variant occurred without transgene expression. At 24 months of age 97% of tau aggregates in cells were without transgene expression which the authors said showed that the spread of the tau variant had increased with age. In each area the tau aggregation pattern of first axon then soma applied.
De Calignon and colleagues demonstrated that axon degeneration in their transgenic mouse model was accompanied by active microglia and gliosis. Glial tau pathology occurs in Alzheimer’s disease where tau inclusions can be found in astrocytes and oligodendrocytes. The presence of human tau protein in GFAP positive astrocytes in the rTgTauEC transgene mouse suggested that release of tau from neurons and uptake by glia also takes place in this mouse model.
The authors also found that cells outside of the entorhinal cortex with no EC input could demonstrate initial transgene expression, but with no tau accumulation. The cerebellum which expresses human P301L tau mRNA, did not develop any somatic neurofibrillary tangles indicating that neuronal cells in this area are protected in some manner to the action of variant tau.
De Calignon and colleagues concluded that their rTgTauEC transgenic mouse model could investigate the path of tau misfolding and neurofibrillary tangle formation beginning in the entorhinal cortex II layer and linked to progressive neurodegeneration and Alzheimer disease type symptoms. Their investigations showed that later development of tau pathology did not require transgene expression of the human tau variant.


There are several reasons why this research is especially interesting. The first is that it appears to provide a definitive link between tau aggregation pathology and the entorhinal cortex and hippocampus areas consistent with memory problems observed in sufferers of Alzheimer dementia illness. It is known that the medial temporal lobe is important for declarative memory consolidation and this includes areas such as the hippocampus, entorhinal cortex, perirhinal cortex (normally known together as the rhinal cortex), parahippocampal cortex and nearby cortical areas. Neuronal pathways connect these areas with other parts of brain. De Calignon and colleagues showed neurodegeneration caused by the variant tau and tau aggregation followed a hierarchy of areas beginning with the entorhinal cortex and this matched the inputs and outputs of the EC area. However, initial seeding of the human tau variant in the work described above was expressed in only a fraction of the EC-II cells with the rest exhibiting at the early stage inhibition to gene expression. The disruption of neuronal cell functioning due to tau pathology leads to loss of connectivity and synchronicity of neuronal firing and hence, formation of declarative memories is affected. This view is especially relevant when the recognized role of the hippocampus in memory formation is considered. The hippocampus is believed to play a significant role in the formation of new memories and spatial memory (sequences) and therefore, tau aggregation and neuronal degradation in this area would have a major effect on memory.
Another factor that makes this work interesting is that the tau pathology appears to be caused by one factor, but then progresses via another mechanism. According to De Calignon and colleagues experiments the tau pathology began with gene expression but then advanced up the hierarchy in a prion like manner. The development was still tau related, but not at the nuclear level. It was suggested that the tau, or a particular species of tau such as hyperphosphorylated tau, misfolded tau, or a fragment of tau, may have been released at the synapse and transferred across the extracellular space to adjacent neurons or between adjacent cells and then internalized. This transmitted the tau misfolding from one cell to another and to inside that cell where it would seed the misfolding of the native tau. Hence, although gene expression began the process, at later times, another method of transfer of tau pathology took place.
There are still so many questions to be answered about the mechanism of Alzheimer disease, many of which cannot be investigated using an animal model, but the availability of such a model can give researchers a chance to investigate how tau and possibly beta-amyloid pathology affects different aspects of neuronal cell function on the small scale and links between brain areas on the larger scale.

Since we`re talking about the subject ………

…..could it be that tau assists with vesicular transport from the mitochondria to the neuronal cell membrane in response to depolarization by providing an alpha neck linker from kinesin to the alpha and beta tubulin helices that make up the microtubule structure? I put forward here a hypothesis of how tau and beta-amyloid are linked in neuronal cell function and hence, how problems with one or other can cause neurodegeneration. The presynaptic membrane would contain sodium, calcium and potassium channels and presynaptic glutamate receptors. Depolarisation of the axon would cause the sodium channels to open and sodium ions to flow in thus causing the inside of the cell membrane to become positive. Microtubules made up of alpha and beta helicals of tubulin stretch from the mitochondria to the cell membrane. The depolarization and subsequent change in membrane polarity is a signal for vesicles full of neurotransmitters to travel down the microtubule since flow is from the minus end at the centre of the cell to positive polarity of the cell membrane. Tau proteins form the link in the form of an alpha neck linker between vesicle, kinesin and the tubulin structure. At the cell membrane, calcium channel opening and calcium influx possibly due to glutamate receptor binding causes the SNARE protein conformational change leading to merging of the vesicle with the membrane structure and exocytosis of the neurotransmitters. These would transverse the synaptic cleft and bind with the appropriate receptors on the postsynaptic membrane. The conformational change caused by the attachment of the vesicle to the membrane (or possibly the action of the potassium channels) causes the amyloid precursor protein sat in the membrane to be split by the secretase enzyme. The beta amyloid formed would be deposited on the external presynaptic membrane close to the vesicle opening. Excess neurotransmitters and metal ions in the synaptic cleft would be attracted by the beta amyloid pleated structure and would bind to it causing a conformational change (and possibly a predominance of hydrophobic regions) that would cause the amyloid pleat and redundant neurotransmitters to be internalized into the vesicle. This would then either remain at the presynaptic membrane or be taken back to the mitochondria up the microtubule by the reverse dynein controlled action where fatty acids would be broken down amongst other molecules to form hydrogen peroxide and the neurotransmitters broken down by monoamine oxidases. This hypothesized version links the tau and amyloid functions and explains the importance of protein synthesis in neuronal functioning and learning. Tau variants could lead to cell degeneration by the dysfunction of vesicular transport of vital neurotransmitters for example and incorrect splitting of the amyloid precursor protein to an inactive amyloid that sits on the outside cell membrane (plaque formation) prevents the return of the cell to the pre-depolarisation state by preventing excess neurotransmitter binding and endocytosis. However, it does not explain how tau pathology progresses according to the De Calignon and team experiments. It is possible that neurodegeneration produces its own necrotic cell death factors that are transferred from cell to cell and the tau effect is a by-product of this. This is only a hypothesized version of what could be happening in the neurons of the perforant pathway. It could explain why other brain areas are not affected in the same way regarding tau pathology and why beta amyloid is required for normal nerve functioning, and only excess levels form plaques.

….is it possible that strengthening the information input across all senses bypasses neuronal cell problems from tau pathology in specific sensory perforant pathways so that memories are formed that appear to be multi-sensory, but are in fact a mix of real-time sensory information (no tau pathology) and activation of previously formed memories to fill the gap (tau pathology).

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