Envisaging Alzheimer's Disease as a Cascade from Amyloid to Inflammation to Tau
Alzheimer's disease is marked by an accumulation of solid deposits of amyloid-β and modified tau protein. It is also an inflammatory condition, like many age-associated diseases, and past evidence suggests that reduced inflammation can improve matters, while greater levels of chronic inflammation are a risk factor for developing Alzheimer's. What is cause and what is consequence in all of this, however? The authors of this study propose that the order of causation is amyloid, inflammation, then tau. If so, then amyloid clearance therapies should be better than anti-inflammatory strategies, as and when they can be made to work effectively in humans.
In the brains of people with Alzheimer's disease, there are abnormal deposits of amyloid beta protein and tau protein, and swarms of activated immune cells. But scientists do not fully understand how these three major factors combine to drive the disease. Researchers exposed immune cells normally found in an activated, inflammatory state in Alzheimer's brains to tiny clusters of amyloid beta - or oligomers, which are believed to be the most harmful forms of the protein. "Our thinking was that the amyloid beta oligomers would activate an inflammatory response in these immune cells, and we wanted to see if this would induce pathological forms of tau when given to neurons."
The researchers then focused on the fluid in which the immune cells had been growing. This fluid, which was filled with inflammatory factors resembled the fluid in which these cells typically live inside human brains. The team added this fluid to cultures of human cortical neurons. The neurons soon developed abnormal, bead-like swellings along their axons and dendrites. This "neuritic beading" has been seen in Alzheimer's patients and has been considered an early sign of neuronal damage, although it hasn't been clear how beading was connected to abnormal tau or if the beading led to Alzheimer's disease. The team then looked for tau in the beads and found a striking accumulation of it, though it was in an abnormal form, modified in a different way than previously thought. This modification is thought by the researchers to cause tau to become aggregated.
The finding of abnormal tau in the neuritic beads indicated that these beads could mark tau's entry into the Alzheimer's disease process. Within the beads, researchers also found high calcium levels, which are known to harm neurons and are considered an important feature of neurons in people with Alzheimer's. "We think these neuroinflammatory factors trigger this cascade. They flood the neuron with calcium. And we think that once the calcium accumulates, it causes tau to become abnormally modified. This probably leads to a snowball effect: tau detaches from microtubules and is trafficked throughout the neuron, ending up in these beads. One possibility is that these tau-filled beads are the sites where the classic tangle-like aggregates of tau will eventually emerge, which is the hallmark of Alzheimer's disease."
Researchers used mass spectrometry to sort out the amyloid beta-induced neuroinflammatory molecules that had triggered the calcium influx and neuritic beading. They were able to show that one protein in particular, MMP-9, was responsible for some of these adverse effects. "MMP-9 is an inflammatory protein shown to be elevated in the brains of Alzheimer's patients. In our study, we show that MMP-9 alone can trigger a calcium influx that floods the neuron." The researchers also identified the protein HDAC6, which originates from within neurons and concentrates in the neuritic beads. Normally, HDAC6 is thought to detect unwanted protein aggregates within neurons and transport them away for disposal. However, blocking HDAC6 stopped nearly all beads from forming in these experiments. Both of these proteins have been found to be elevated in affected areas of Alzheimer's brains. Drug companies are now developing and testing HDAC6 inhibitors, which have performed surprisingly well in early studies, although it has not been fully understood how these inhibitors work. "Our work might explain why HDAC6 inhibitors have shown such early promise."