An Alzheimer’s disease protein seems to spread via synapses

For what seems like forever, medical scientists have been trying to figure out the relative disease-causing importance of two types of protein often found in the brains of Alzheimer’s disease (AD) victims: tau and amyloid-beta (Aβ). While the larger question is still unresolved, recent research may have made a significant discovery about the tau protein.

The research indicates mechanisms involved in the very early stages of AD, so it may lead to diagnostic tests that can signal the beginnings of the disease long before symptoms become apparent. This might allow for timely applications of preventive therapies, and might even contribute to the discovery of such therapies.

Tau is associated with Alzheimer’s because it is found in the form of neurofibrillary tangles (NFTs) in the neurons of the autopsied brains of Alzheimer’s victims. (Such tangles are also found in neurons affected by other neurodegenerative diseases. Collectively these diseases are called tauopathies.)

There are several variant forms of tau (“isoforms“) produced by alternative splicing of a single gene, MAPT (microtubule-associated protein tau). As the name implies, the various isoforms have functions related to microtubles, which make up the framework (“cytoskeleton“) of cells. In general, the different isoforms help stabilize microtubles in different parts of a cell. When tau abnormally forms tangles it is no longer able to hold microtubles together properly, so the microtubules disintegrate, and the cell eventually dies.

The root cause of NFT formation isn’t known, although Aβ is strongly suspected of having something to do with it, since plaques consisting of Aβ build up around the neurons in brains of Alzheimer’s victims. However, it is known that the proximal cause of NFT formation is the hyperphosphorylation of normal tau by the attachment of many phosphate groups. This alters the shape of tau proteins and allows them to become tangled clumps that can’t stabilize microtubules.

Autopsied AD brains show that NFT formation proceeds in stages (“Braak stages”) according to regions of the brain that are affected. In the early stages NFTs are found primarily around the entorhinal cortex (EC), a small region on the underside of the brain. The EC is the main interface between the hippocampus, which is of primary importance in memory formation, and the neocortex, which covers much of the outside of the brain and is the host of many higher cognitive functions. The NFTs spread to the hippocampus in the middle stages of AD, and eventually reach the neocortex in the late stages.

This regularity of the spread of NFTs through neurons in AD seems like an important clue to an understanding of how the disease progresses. In particular, the EC is one of the first areas affected in AD, and it is connected by single synapses to neurons of several areas of the hippocampus: the dentate gyrus (DG), the subiculum (SUB), and regions CA1 and CA3. (This set of connections is called the “perforant pathway“.) The EC also has single-synapse connections to the parahippocampal cortex and the perirhinal cortex, which in turn connect (through a series of synapses) with the temporal and parietal lobes of the neocortex.

This predictable pattern of NFT spreading suggests that a signal of some sort may pass directly through synapses. The main alternative hypothesis would be that NFTs show up in other areas that are initially not as susceptible to whatever factors cause NFTs to appear in the EC to begin with (presumably involving Aβ).

In order to test the synaptic transmission hypothesis, the new research used genetically engineered mice (“NT mice”) that were equipped with genes to encode a pathological form of human tau specifically in the EC. In order to provide experimental controls, production of human tau required an inducing agent in order to be switched on. Several antibodies can be used to show the presence of the abnormal human tau in samples of brain tissue.

In brain tissue from young (10-11 months) NT mice with human tau switched on, antibodies showed presence of this tau in cells of the EC and in cells of the hippocampus at the end of the perforant pathway, connected by a single synapse to cells of the EC. Control NT mice in which human tau genes were present but not expressed showed negligible amounts of human tau anywhere, as expected.

The situation was very different in brain tissue from old (22 months) NT mice. At that point antibodies showed the abnormal tau had reached cells deeper inside the hippocampus and in cells in parts of the neocortex. Such cells are all more than one synapse away from neurons in which the human tau was initially expressed. This pattern of spreading resembles what’s found in human AD brain tissue.

A variety of other tests were performed to check the results and rule out other possible explanations for what was observed. For example, examination of specific cells outside the EC but connected to it by a single synapse showed higher levels of human tau in older mice compared to younger ones. In addition, there was a tendency for tau to show up increasingly in the central regions of neurons as well as in the axons where it is more normally found. Such a development is also observed in early stages of human AD.

Another sort of test showed that heavily phosphorylated tau was especially more likely to have spread in older mice than in younger ones. In advanced stages of human AD, abnormal tau that is insoluble, malformed, hyperphosphorylated, and incorporated in neurofibrillary tangles is a characteristic sign. It’s associated with neurodegeneration and cell death, although exactly which of these abnormalities are responsible for the pathology isn’t clear.

A specific type of stain that indicates presence of tangles revealed some evidence for tangles in neurons of older NT mice, but not in younger ones, or in any of the control mice. Another stain that was sensitive to malformed tau gave similar results.

What still is not clear is how tau might be transmitted across neural synapses. Such transmission is perfectly normal for neurotransmitters, because that’s the basic mechanism by which neurons communicate with each other. However, neurotransmitters are small peptides (short chains of amino acids connected by peptide bonds), while all forms of tau are full proteins (much longer amino acid chains). The mechanism might involve release by cells of exosomes containing tau, as other recent research suggest is possible. (Exosomes are containers for proteins, similar to synaptic vesicles which normally carry neurotransmitters.)

All this will surely be an area for much more research. Another study similar to the one described here is known to be in the publication pipeline.

The research paper sums up its conclusions nicely:

In general, our NT mouse model replicates the spatial and temporal aspects of the earliest stages (I–III) of Braak staging of tauopathy in Alzheimer’s disease. We have demonstrated that tau pathology initiating in the EC can spread to other synaptically connected brain areas as the mice age, supporting the idea that AD progresses via an anatomical cascade as opposed to individual events occurring in differentially vulnerable regions. Thus, our NT transgenic mouse provides a model in which the spatial and temporal propagation of the disease can be predicted, and correlative functional outcomes can now be tested. Given that the earliest Braak stages are not associated with cognitive decline, identifying an EC based “biomarker” for pathology or dysfunction and developing therapeutic strategies to prevent propagation are likely to be both possible, and beneficial.

Liu, L., Drouet, V., Wu, J., Witter, M., Small, S., Clelland, C., & Duff, K. (2012). Trans-Synaptic Spread of Tau Pathology In Vivo PLoS ONE, 7 (2) DOI: 10.1371/journal.pone.0031302

Further reading:

Study Shows Alzheimer’s Disease May Spread by ‘Jumping’ from One Brain Region to Another

Path Is Found for the Spread of Alzheimer’s

Alzheimer’s Disease Protein Spreads Through Neurons in Mice

Study gives new clues on how Alzheimer’s spreads

Mouse Study Suggests Alzheimer’s Spreads Through Brain Like an Infection

Alzheimer’s Spreads Like a Virus From Neuron to Neuron, Studies Show

US study finds Alzheimer’s spreads like infection

Alzheimer’s disease “jumps” across brain cells to spread

Alzheimer’s protein – no, not amyloid and of course no prion – may spread through brain like infection

Trans-Synaptic Spread of Tau Pathology In Vivo

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