A step closer to understanding how brain cells die in Alzheimer's disease

01 June 2018
Arrows point to neurofibrillary tangle-like structures
New research from the Australian Institute for Bioengineering and Nanotechnology at the University of Queensland in collaboration with the Centre for Stem Cell Systems at the University of Melbourne, has brought us a step closer to understanding how protein clumps called amyloid plaques contribute to the death of brain cells in Alzheimer’s disease. 

The research, published in the highly regarded journal Stem Cell Reports, shows that, surprisingly, an increased production of plaques does not lead to an increase in brain cell (neuron) death. This suggests that the plaques commonly found in dementia don’t kill neurons directly or, if they do, they don’t work alone. 

Currently, Alzheimer’s disease effects around a quarter of a million Australians, accounting for more than two-thirds of all age-related dementia cases. 

One of the major hallmarks of Alzheimer’s disease is the accumulation of the so-called ‘beta-amyloid plaques’. These plaques are formed when a type of protein in the brain, called amyloid precursor protein (APP), is broken down into smaller fragments. These fragments, which are called beta-amyloid, then clump together to form plaques. 

It is widely thought that these amyloid plaques contribute to the death of neurons in people with Alzheimer’s, either directly, or by causing another protein, called tau, to form toxic ‘neurofibrillary’ tangles. Thus, reducing amyloid plaques has been the focus of many efforts to treat the condition. 

To get a better understanding of the role APP and amyloid plaques play in neuron death, AIBN researcher Professor Ernst Wolvetang and colleagues used stem cells from people with Down syndrome because they generally develop early onset Alzheimer’s disease. 

“People with Down syndrome have an extra copy of chromosome 21, and therefore carry an extra copy of the amyloid precursor protein (APP) gene,” says lead author Dr Dmitry Ovchinnikov

The researchers were able to grow neurons from the Down syndrome stem cells and then use the gene editing tool CRISPR to manipulate levels of this protein in these neurons. Careful analysis of the genes affected by the extra copy of APP showed widespread impact on neuronal development and function.

“Current therapeutic focus is on reducing plaques, but the dose of APP itself has a broad effect on the activity of genes in neuronal cells” said Professor Christine Wells, who led the computational analysis from the University of Melbourne.

 “Our data challenge the current dogma in the field that amyloid plaques are sufficient to cause neurodegenerative changes associated with Alzheimer’s disease,” Professor Wolvetang said. 

“The research highlights that human stem cell-based disease modelling in the dish can provide new insights into the molecular mechanisms that conspire to cause Alzheimer’s disease”, he continued, “and, excitingly, this now opens the way for drug screening.”

The study was conducted with financial support from NHMRC and the ARC Special Research Initiative, Stem Cells Australia.  

Professor Ernst Wolvetang and Professor Christine Wells are Chief Investigators at Stem Cells Australia.