Summary: Using zebrafish models, researchers detected genes with altered levels of expression. The genetic variations were associated with abnormalities with mitochondrial function and the production of ATP.
Source: University of Adelaide
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.
The first short paper from the University of Adelaide’s Alzheimer’s Disease Genetics Laboratory on their Alzheimer’s disease-like mutant fish was published on 3 May in the journal Molecular Brain.
Thanks to Michael Lardelli for submitting this neuroscience research news for inclusion.
University of Adelaide
Michael Lardelli – University of Adelaide
The image is credited to The University of Adelaide.
Original Research: Open access
“Brain transcriptome analysis of a familial Alzheimer’s disease-like mutation in the zebrafish presenilin 1 gene implies effects on energy production”. Newman M, Hin N, Pederson S & Lardelli M.
Molecular Brain. doi:10.1186/s13041-019-0467-y
Brain transcriptome analysis of a familial Alzheimer’s disease-like mutation in the zebrafish presenilin 1 gene implies effects on energy production
To prevent or ameliorate Alzheimer’s disease (AD) we must understand its molecular basis. AD develops over decades but detailed molecular analysis of AD brains is limited to postmortem tissue where the stresses initiating the disease may be obscured by compensatory responses and neurodegenerative processes. Rare, dominant mutations in a small number of genes, but particularly the gene PRESENILIN 1 (PSEN1), drive early onset of familial AD (EOfAD). Numerous transgenic models of AD have been constructed in mouse and other organisms, but transcriptomic analysis of these models has raised serious doubts regarding their representation of the disease state. Since we lack clarity regarding the molecular mechanism(s) underlying AD, we posit that the most valid approach is to model the human EOfAD genetic state as closely as possible. Therefore, we sought to analyse brains from zebrafish heterozygous for a single, EOfAD-like mutation in their PSEN1-orthologous gene, psen1. We previously introduced an EOfAD-like mutation (Q96_K97del) into the endogenous psen1 gene of zebrafish. Here, we analysed transcriptomes of young adult (6-month-old) entire brains from a family of heterozygous mutant and wild type sibling fish. Gene ontology (GO) analysis implies effects on mitochondria, particularly ATP synthesis, and on ATP-dependent processes including vacuolar acidification.