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Jesús Avila*
1Centro de Biologia Molecular “Severo Ochoa” (CSIC-UAM), Madrid, Spain
2Centro de Investigación Biomédica en Red de Enfermedades neurodegenerativas (CIBERNED), Madrid, Spain
Received date: March 27, 2012; Accepted date: March 28, 2012; Published date: March 30, 2012
Citation: Avila J (2012) Spreading of Tau Pathology. J Alzheimers Dis 2:e110. doi:10.4172/2161-0460.1000e110
Copyright: © 2012 Avila J. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Alzheimer disease usually starts with cognitive impairment and memory loss that could be the consequence of the loss of neuronal function at the entorhinal cortex and hippocampal region. From those brain areas the disease spreads to surrounding neurons in extra hippocampal regions such as neocortical areas. Disease progression could be followed by searching tau pathology, identified by intracellular tau phosphorylation and tau aggregation. This process also starts at the entorhinal cortex-hippocampal region and further progresses to neocortical areas [1]. By trying to identify potential candidate proteins involved in the spreading of tau pathology, extracellular tau itself appeared as the responsible agent [2]. It was hypothesized that during the progression of the disease, neuron loss occurs and intracellular tau could be released to the extracellular space to become the spreading agent of the pathology, probably after binding to some specific cellular receptors. To test that hypothesis, tau protein was added to neuronal cell cultures, resulting in an increase in intracellular calcium [2] that can be toxic and eventually lead to cell death [2]. Furthermore, by using cell models, it was found that extracellular tau binds to some specific cell membrane receptors, the muscarinic M1 and M3 receptors [3,4]. Tau spreading has also been reported to take place in the absence of neuron death in an exocytosis-endocytosis manner in cell models. It was described that extracellular tau aggregates can be endocytosed by cells and can induce the formation of new tau aggregates that will be released by exocytosis and taken back by other cells by endocytosis in a continuous cycle [5-7]. An increase in intracellular calcium may also result in the secretion of proteins by exosome-like vesicle particles. In summary, a rise in intracellular calcium levels, which can be induced by activation of metabotropic receptors (e.g. muscarinic M1 and M3), may lead to an increase in extracellular tau, either by exocytosis or by neuronal death [3,4].
Using a mouse model to test tau propagation in vivo, Clavaguera et al. [8] injected brain extracts, containing human tau in aggregated form, intracerebrally into wild type or transgenic mice. These mice expressed human tau bearing a mutation found in some patients with a tauopathy, frontotemporal dementia. This mutation facilitates tau aggregation. These experiments demonstrated that tau is propagated from the injection point to surrounding areas, only in transgenic mice but not in wild type mice. Some structural differences, found between both human and mouse tau might be responsible for the distinct results found in wild type and transgenic mice. However, the authors argued that the differences were most likely due to the fact that the used human tau has a higher capacity to aggregate. They also suggested that tau aggregates but not monomeric tau are involved in disease spreading. Of note, contrary to these results obtained in mice, in cell models, mainly monomeric tau but not aggregated tau seems to be the toxic agent [3,4].
More recently, the analysis of tau spreading in neurodegenerative diseases in vivo has been extended in two very similar recent papers from two different groups [9,10]. One of these publications was even quoted in the New York Times. Both studies were performed in the same mouse model, a conditional transgenic mouse overexpressing human tau (with the same mutation used in reference [8]. Human tau was expressed under the control of the neuropsin promoter, which is mainly expressed at the entorhinal cortex. In both papers, it was tested whether the propagation of tau pathology occurs starting from the entorhinal cortex in a similar fashion to that reported for Alzheimer disease patients [1]. By using very similar experimental approaches, the two articles describe a progressive tauopathy radiating from the entorhinal cortex to neighbouring areas. Since the surrounding cells to those expressing human tau may be synaptically connected to them, both articles suggest that tau can be mainly transferred to those neighbouring cells that are synaptically connected, and that a trans-synaptic spread of tau pathology in vivo is occurring. However, the molecular mechanism of synaptic transmission involved was not clarified. A possible explanation for this process can be found in previous reports that showed that extracellular tau could interact with muscarinic receptors, as mentioned above [3,4]. Furthermore in Alzheimer disease, cholinergic neurons are the most damaged ones [11].
However, some criticisms for the two recent in vivo articles may arise because the neuropsin promoter, used in both studies, may also work in other brain regions besides the entorhinal cortex. De Calignon et al. [10] showed that this is not the case since in neurons from the entorhinal cortex, both human tau mRNA and human tau protein were present, whereas in neurons of the surrounding areas only the protein but not the mRNA was present.
Up to now, in all the mentioned reports, either cellular or animal models were used. Thus, the next question would be: What happens in Alzheimer disease patients? In a recent paper, by analyzing tau protein present in cerebrospinal fluid of Alzheimer disease patients, two tau populations were found, one in which tau was present in exosome-like vesicle particles and the other one containing uncoated tau that just may arise from neuron death. The first population is mainly present at the first stages of the disease whereas the second one increases with the development of the neurodegeneration [12]. Vesicle secreted tau may arise due to the excess of tau protein that takes place in Alzheimer disease and could be toxic for neurons, as recently suggested [13]. When toxicity further increases, neuron death might occur and intracellular monomeric tau could be released to the extracellular space. This extracellular tau may react with muscarinic receptors leading to an increase in intracellular calcium levels that can in turn result in new cell death or in the secretion of exosome-like vesicles containing tau protein. This working hypothesis should be further analysed. It should also be tested why only positive results were reported, for tau transmission in transgenic mouse models over expressing human tau bearing the same mutation.
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