If there was a poster child of aging diseases, it would be Alzheimer’s disease. The brains of people suffering from Alzheimer’s disease have deposits of amyloids resulting from the loss of proteostasis. Alzheimer’s disease is accompanied by the presence of amyloid beta protein and tau protein as well as large numbers of activated pro-inflammatory immune cells.
The debate about which is primary has raged for many years in the research world, and it is still not clear how these three elements combine to cause disease progression. A new study has attempted to untangle the mystery and suggests the order is beta amyloid, inflammation, then tau, and this study identifies new targets for therapies.
New Research shows how Alzheimer’s may progress
The research team demonstrated in human cell cultures how amyloid beta triggers an excessive inflammatory response in immune cells, which then leads to damage to neurons. Next, they showed how this neuron damage causes the development of bead-like formations packed with tau protein. These bead-like formations are typically observed in the brain cells of people with Alzheimer’s disease.
The study started by exposing the same kind of immune cells that are found in an activated state in Alzheimer’s brains to clusters of amyloid beta. The researchers believed that this exposure would induce an inflammatory response from the immune cells, as other research in the past suggested. They wanted to see if this exposure would lead to the creation of pathological tau when given to neurons.
After exposing the immune cells to the beta amyloid clusters, they then examined the fluid the cells had been growing in. The fluid was filled with a cocktail of proinflammatory factors, confirming that exposure to beta did indeed provoke an immune response. The mixture of factors in the culture closely resembled those present in the brains of people with Alzheimer’s.
The next step saw the team take this inflammatory fluid and add it to cultures of human neurons. Very quickly, the neurons developed the same bead-like structures along their axons and dendrites that are observed in Alzheimer’s. This beading has previously been considered an early sign of neuron damage, though it was not clear if the beading was connected to tau or caused Alzheimer’s disease. They looked for tau in these beads and discovered a great deal of it was present, though this was in an abnormal form different to the type of tau typically seen in Alzheimer’s patients. This particular form of tau was modified in a way not previously seen. The researchers in the study believe that this modification is what causes the tau to become aggregated.
Tau proteins normally provide structural support to the microtubules, which transport molecules along the axons in a neuron. In Alzheimer’s patients, these tau proteins are different and it has never been clear why. In the disease, abnormal tau is detached from the microtubules and clumped into long and tangled threads of aggregates. It is unclear if these tau tangles directly damage the neurons; however, previous studies suggest that the loss of tau from the microtubules and resulting disruption to axon molecule transport does cause severe damage to the neuron.
The discovery of abnormal tau in these bead-like formations suggests that the beads could be where tau enters the disease process. The beads were found to contain high levels of calcium, which is known to damage neurons and is a typical feature in the neurons of Alzheimer’s patients.
The research team believes that the inflammatory factors trigger this process and fill the neuron with calcium. Once this calcium accumulates to high levels, it alters the tau in the microtubules, making it abnormal. It is likely that once this happens, the tau then becomes detached from the microtubules and travels through the neuron to form the bead-like structures. The beads may be where tau tangles eventually develop, leading to a classic sign of Alzheimer’s progression.
New targets for preventing Alzheimer’s
During the study, the researchers identified two proinflammatory proteins produced by the immune cells exposed to beta – MMP-9 and HDAC6 – that help facilitate this deadly cascade of beta amyloid, inflammation, and tau. By targeting these key proteins in the process, the researchers hope they could prevent the process occurring in order to treat or even prevent Alzheimer’s completely.
They found that the protein MMP-9, in particular, played a key role in triggering the process that leads to calcium intake and the formation of beads. They discovered that the MMP-9 protein alone was able to trigger the calcium overload that led to the progression of damage to the neuron and ultimately to the formation of tau tangles.
The other molecule they looked at was HDAC6, which is present in neurons but is focused in the bead-like formations. It was thought that HDAC6 detects protein aggregates in the neuron and disposes of them; however, when the researchers blocked HDAC6, it actually prevented almost any beads from forming during their experiment.
Both MMP-9 and HDAC6 are found in increased levels in Alzheimer’s brains. Some drug companies have tested HDAC6 inhibitors, and the early-stage results have been promising. The researchers here believe that their work explains why HDAC6 inhibitors have shown such promise so far.
It has long been suspected that Alzheimer’s is not a one-way process, and this study takes another step closer to that. Alzheimer’s is caused by one of the hallmarks of aging and, in principle, should be reversible just like any of the other aging hallmarks.
 Tseng, Jui-Heng et al.(2017) The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology. Cell Reports , Volume 20 , Issue 9 , 2169 – 2183