Scientists have confirmed that buildup of beta-amyloid plaques in the brain is the first step in a process that leads to Alzheimer’s disease.
Using a gel-based, 3-D culture system, researchers have for the first time succeeded in reproducing the full course of events underlying the development of Alzheimer’s disease.
Researchers from the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) found the first clear evidence supporting the hypothesis that deposition of beta-amyloid plaques in the brain is the first step in a cascade leading to the devastating neurodegenerative disease.
They also identified the essential role in that process of an enzyme, inhibition of which could be a therapeutic target.
“Originally put forth in the mid-1980s, the amyloid hypothesis maintained that beta-amyloid deposits in the brain set off all subsequent events – the neurofibrillary tangles that choke the insides of neurons, neuronal cell death, and inflammation leading to a vicious cycle of massive cell death,” said Rudolph Tanzi, director of the MGH Genetics and Aging Research Unit.
“One of the biggest questions since then has been whether beta-amyloid actually triggers the formation of the tangles that kill neurons.
“In this new system that we call ‘Alzheimer’s-in-a-dish,’ we’ve been able to show for the first time that amyloid deposition is sufficient to lead to tangles and subsequent cell death,” he said.
The MGH team used the gel-based, three-dimensional culture system to grow human neural stem cells that carried variants in two genes – the amyloid precursor protein and presenilin 1 – known to underlie early-onset familial Alzheimer’s Disease(FAD).
Both of those genes were co-discovered in Tanzi’s laboratory.
After growing for six weeks, the FAD-variant cells were found to have significant increases in both the typical form of beta-amyloid and the toxic form associated with Alzheimer’s.
The variant cells also contained the neurofibrillary tangles that choke the inside of nerve cells causing cell death.
Blocking steps known to be essential for the formation of amyloid plaques also prevented the formation of the tangles, confirming amyloid’s role in initiating the process.
The version of tau found in tangles is characterised by the presence of excess phosphate molecules.
PTI