Searching for Hidden Causes of Alzheimer’s Disease: Can Tiny RNA Snippets Shed Light on a Growing Problem?

By Dieter Edbauer, Ludwig-Maximilians-Universität Munich

‘I’m so stressed!’ or ‘it’s just old age!’ are reassuring excuses that seniors may give themselves when they notice difficulties in recalling new memories. But deep inside, many are worried it might be Alzheimer’s and will go to great lengths to conceal their memory problems from friends and family. In the sad case of Alzheimer’s disease, this won’t be possible for long. As more memories get lost, mood swings and aggression set in, and patients gradually lose their independence and control over their bodily functions. By then the brain is filled with toxic deposits called plaques and tangles, consisting of the two proteins Ab and tau, respectively. Many neurons have lost synaptic connections or have died altogether, resulting in a shrunken brain. Unfortunately there is still no cure and current treatments are only moderately effective.

For the last 20 years, research on Alzheimer’s disease has focused on a handful of cellular proteins. Mutations in these proteins were initially found in patients with rare but highly aggressive heritable forms of Alzheimer’s with an early onset (younger than 60 years). All these mutations seem to regulate production or clearance of the so-called amyloid beta peptide (Ab), which is the main component of plaque deposits in the brain of Alzheimer’s patients. However, even in healthy brains, A is constantly produced by cleavage of the amyloid precursor protein known as APP. My research, in conjunction with the research of Christian Haass and Harald Steiner at the Ludwig-Maximilians University in Munich, focuses on the presenilins, two homologous proteins often mutated in early-onset Alzheimer’s disease. We have shown that presenilins, together with three additional proteins, assemble into molecular scissors that cleave APP. The released Ab can then deposit into plaques. Unfortunately, we now know that the cleavage of dozens of other proteins by this enzyme is necessary for healthy life. A clinically useful drug would have to inhibit only toxic A-production in order to avoid the disastrous side effects of unspecific blockage.

Focusing on inherited forms of the disease helped to uncover a chain reaction of molecular events that can cause Alzheimer’s disease. Transferring mutant forms of APP and presenilins into mice causes plaque pathology and memory deficits reminiscent of early Alzheimer’s disease. For a long time this suggested that our theory about Alzheimer pathogenesis is correct, and an effective therapy just a matter of time and money. However, many drugs that had shown promise in mice had no effect — or even severe side effects — in humans. Therefore, many scientists now argue that the drugs would need to be given even earlier (and be more specific). Moreover, mice that produce human mutant proteins show very little neuronal death and no tangle pathology, the other two hallmarks of Alzheimer’s disease besides A plaques. This strongly suggests that we are a missing a fundamental piece in our understanding of the disease. Additionally, in most patients these key proteins do not contain mutations, and it remains unclear how the deadly cascade is initiated anyway. From twin studies elsewhere we know that the more common late-onset Alzheimer’s disease is also highly heritable; however, only one genetic variation with a strong effect, known as ApoE4, has been identified so far.

What could we have overlooked in decades of research? So far we have focused predominantly on cellular proteins and the genes that encode them. Although the main function of the human genome is to store the blueprints for protein synthesis, the majority of our DNA does not actually encode proteins. For a long time this has been regarded as prehistoric junk. Now, accumulated evidence suggests this may have been wrong.

Apparently most of this ‘junk’ DNA is still transcribed into RNA — normally a short-lived messenger for protein production. However, even RNA not coding for proteins can serve a purpose. A family of about a thousand short RNA molecules/snippets, hence called microRNAs, is able to regulate the production of many cellular proteins at once. The changes on each individual protein are typically small but together they can have dramatic consequences. The amounts of several of these microRNAs are altered in brains of late-onset Alzheimer’s disease patients. With Morgan Sheng and others at MIT in Cambridge, Massachusetts, I found that increasing the amounts of the microRNA known as number 125b as observed in patients weakens the synaptic connections between cultured neurons. Chronically this could even lead to synapse loss, one of the earliest findings in Alzheimer’s. My lab is now investigating the effects of other dysregulated microRNAs on neurodegeneration and other aspects of Alzheimer pathology, and the initial results are promising.

Apart from microRNAs, there are many unknown RNA molecules that might be altered in Alzheimer brains. It will be even harder to decipher their role in the disease because little is known about their function or mode of action. However the effort might be worthwhile, since most disease-associated genomic variations in Alzheimer’s and many other diseases don’t directly affect protein sequence. Therefore my work is now focused on the 95% ‘dark matter’ in the human genome that is not translated into proteins but may regulate cellular protein expression during aging and thus cause Alzheimer’s disease.

 

Dieter Edbauer
Ludwig-Maximilians-Universität Munich
www.atomiumculture.eu