Alzheimer’s disease is one of the most common diseases of the brain and whilst we may not yet have any decent therapies for preventing its progression, our understanding of its pathogenesis is growing and it seems likely that soon new pharmacotherapies will arrive. In this article I want to describe the process that leads to neurodegeneration in Alzheimer’s disease in all its gruesome biochemical detail and then highlight the points where future drugs may act.
So what causes Alzheimer’s disease? Well the only currently used method to diagnose a case of dementia as Alzheimer’s disease is post mortem histology (how jolly). If you look at the brain tissue of someone who had Alzheimer’s disease under the microscope, you see two characteristic features. The first is something called extracellular Amyloid Beta plaques. These are effectively lumps of gunk amongst the neurons. The second key feature is that amongst the normal looking neurons you will see some neurons which have massively distorted cell bodies, which are bursting full of tiny fibres. These cells are known as neurofibrillary tangles. The Amyloid Beta plaques and Neurofibrillary tangles are the pathognomonic features of Alzheimer’s disease and are believed to be responsible for the cognitive and memory losses seen in people with Alzheimer’s disease.
I now want to try and explain what we know about where the Amyloid Beta plaques and Neurofibrillary tangles come from. It all starts with a protein called Amyloid Precursor Protein or APP for short. You can visualise APP as a rod. Now APP is usually cut in half by an enzyme called alpha Secretase. Now this is the good pathway. Indeed the two products as far as we know don’t cause any problems. However there is another enzyme given the fantastic name Beta Secretase, which again cuts the enzyme into two but it cuts it off centre so that one fragment is longer than it would be when alpha Secretase does the cutting and the other fragment is shorter. The fragment which is now shorter, which is called the sAPP for secreted Amyloid Precursor protein, doesn’t cause a problem. But the fragment which is now longer does. This longer fragment can be cleaved into two pieces again, by yep you’ve guessed it gamma Secretase and one of the final fragments it produces is the nasty bit which is going to form the Amyloid Beta plaques.
Now gamma Secretase can actually cut this final fragment in one of two places. If it cuts in the first place it produces Amyloid Beta 40 protein fragment along with a second piece that we’re not interested in. And if it cuts at the fragment at the second of the two places it produces a slightly longer fragment called Amyloid Beta 42 along with a slightly shorter second piece. It is these two proteins Amyloid Beta 40 and 42 which aggregate together to form Amyloid Beta plaques. It is speculated that Amyloid beta plaques form throughout your life and you only get symptoms of Alzheimer’s disease once you have enough neurodegeneration for deficits to begin. The tendency of Amyloid Beta 42 to form plaques is slightly greater than that of Amyloid beta 40. Hence the gamma Secretase enzyme which your body produces may determine whether you get Alzheimer’s disease in your life or not, since if your enzyme prefers to cleave at the second site over the first you will accumulate plaques quicker.
The first thing to say is that we could use this to diagnose someone with dementia with Alzheimer’s disease whilst they were alive. Indeed by taking a lumbar puncture and measuring levels of Amyloid beta 40 and 42 you could make that diagnosis. However this is not currently done because knowing that this process is the cause of their dementia would not effect the treatment that they receive. This is because at present all drug treatments is symptomatic rather than actually preventing the progression of the disease. It is hoped that in the future we will have drugs which can actually prevent the aggregation of Amyloid Beta 40/42 to form Amyloid Beta plaques. Current drugs which are not yet approved for human used which w believe do this are cyclohexanehexols, tramiprosate and Solanezumab. Solanezumab is a fully humanized monoclonal antibody (that’s what the umab on the end of its name means) which binds to Amyloid Beta 40/42 to hopefully prevent them aggregating. Unfortunately its recently failed phase 3 drug trials.
Ok so that is where the Amyloid Beta plaques come from, what about the Neurofibrillary tangles? Well the tangled fibres within neurofibrillary tangles are a protein called tau protein, more specifically they are phosphorylated tau protein. It is this phosphorylation which allows them to aggregate together in the way that they do within neurofibrillary tangles. When amyloid Beta plaques start forming it is speculated that their presence activates other enzymes called kinases, which add this phosphate group onto the tau proteins. Hence it is believed that the neurofibrillary tangles form as a result of the Amyloid Beta plaques.