We have no clear idea of why Alzheimer’s disease occurs. Many think the disease process begins decades before memory and cognition problems become evident, but how and why does it start? The idea that the disease is caused by an accumulation of the amyloidβ peptide still dominates the thinking of most researchers, but no explanation is readily available for why amyloidβ accumulation begins. And drugs that remove amyloidβ from diseased brains do not halt cognitive decline.
Frustrated by the research field’s lack of progress, a small group of geneticists at the University of Adelaide has taken a different approach. They disregarded the current ideas, theories and models and decided simply to recreate, as closely as they could, the genetic state of someone who has inherited a mutation that will cause an early form of Alzheimer’s disease.
The majority of the mutations that cause an early onset, familial (inherited) form of Alzheimer’s disease are found in the gene PRESENILIN 1 (PSEN1). Most people with PSEN1 mutations carry one mutated copy of the gene and one normal copy. Therefore, the Adelaide researchers generated animals with one mutated copy of the PSEN1 gene. Instead of using mice, they used the versatile (and increasingly popular) zebrafish. This allowed them to examine the brains of large numbers of closely related individuals (siblings) living together in a very similar environment (the same fish tank). By analyzing genetically very similar individuals living under the same conditions they could minimize extraneous differences and focus on the effects of the mutation.
When the fish were young adults (at an age at which humans would not yet have the disease), they analysed brain transcriptomes (the collection of all expressed genes) from mutant fish and their normal siblings. They detected genes with altered levels of expression. Computer analysis of those genes predicted abnormalities in the function of mitochondria and the production of ATP (the “energy currency” of cells). Since energy production underpins all other brain functions, problems in energy production would have widespread consequences.
So what’s next for the Adelaide team? They have generated a number of other fish with different Alzheimer’s disease-like mutations. They want to compare the brain transcriptomes of all of these mutants to find the defect they have in common. That could identify the key problem driving Alzheimer’s disease. Will it be ATP production or something more subtle? Time will tell.
