Researchers one step closer to cracking Alzheimer’s puzzle

 

Research groups at TIFR, Mumbai, IISc, Bangalore and the University of Toronto working together, may have gotten the closest yet to figuring out how the toxic form of the Alzheimer’s molecule looks. Alzheimer’s disease is a progressive form of dementia that is characterised by loss of short-term memory, deterioration in behaviour and intellectual performance, besides slowness of thought. It may occur in middle age or in old age, and while a lot of research is on for drug treatments, none has been successful.

While it is widely accepted that a specific form of the Amyloid beta molecule is a major player in causing Alzheimer’s, the shape and form of this remained elusive, experts say. The excitement now is that scientists have caught a glimpse of the molecule during its attempt to enter a cell membrane, using a new method involving laser light and fat-coated silver nanoparticles. “It is a rare protein and is difficult to probe. It was slightly fortuitous that we found it, using a modified version of Raman Spectroscopy. Usually the signal from this is weak, but we mimicked the cell’s outer layer by encasing silver nanoparticles in a fat membrane,” says Sudipta Maiti, of TIFR, who co-directed the research with P.K. Madhu. The Amyloid beta molecules were fooled into piercing this ‘membrane’ and the nanoparticles enhanced the signals, allowing scientists to see it at that point. When proteins aggregate, or gang up to form a structure, they shift shapes. “At some stage of ganging up they suddenly start attacking the cell membrane and that’s where toxicity begins. How they enter the membrane, and what they look like when entering the membrane is key,” he says.

The ‘lock’ looks like a bunch of Amyloid beta molecules each in the shape of a hairpin, but with a twist, TIFR has said in a release. Debanjan Bhowmik, the lead contributor of the study, says “This has been suspected earlier, but what we found was an unexpected twist in the structure, now becoming a beta-hairpin — very different from the typical hairpin structure people imagined.” This technique might also help in finding the shape of similar proteins in future, Dr. Maiti adds.

The findings were published in the journal ACS Nano this week.

If indeed it turns out to be the ‘lock’ for Alzheimer’s then the discovery will facilitate new efforts to finding a key — an intelligent drug candidate designed to attack the lock. “We have been working on the project for nearly 12 years now, and it is only now that we have started working with a few colleagues from the Institute of Chemical Technology who have the expertise in the field of intelligent design of drug molecules,” Dr. Maiti says.

“The use of technology to identify peptides and peptide transformations, which helps us understand the structure in great detail, is important — both for definitive diagnosis and definitive treatments. Once defined, researchers could adopt the technique to study wider samples, and this will lead to a greater understanding and modification of processes, eventually to better clinical care,” says Ennapadam S. Krishnamoorthy, Chennai-based senior neuropsychiatrist, and founder, Neurokrish. 

                                                                                     source-The Hindu

Gene critical for brain development identified

 

Researchers have identified a gene which is required for the proper development of a healthy cerebellum, a master control centre in the brain for balance, fine motor control and complex physical movements.Researchers have found that a specific gene, called Snf2h, plays an important role in the development of the cerebellum.Athletes and artists perform their extraordinary feats relying on the cerebellum. The cerebellum is critical for the everyday tasks and activities that we perform, such as walking, eating and driving a car.By removing Snf2h, researchers found that the cerebellum was smaller than normal, and balance and refined movements were compromised.Led by Dr. David Picketts, a senior scientist at the Ottawa Hospital Research Institute and professor in the Faculty of Medicine at the University of Ottawa, the team described the Snf2h gene, which is found in our brain’s neural stem cells and functions as a master regulator.

When they removed this gene early on in a mouse’s development, its cerebellum only grew to one-third the normal size.It also had difficulty walking, balancing and coordinating its movements, something called cerebellar ataxia that is a component of many neurodegenerative diseases.“As these cerebellar stem cells divide, on their journey toward becoming specialised neurons, this master gene is responsible for deciding which genes are turned on and which genes are packed tightly away,” said Picketts.“Without Snf2h there to keep things organised, genes that should be packed away are left turned on, while other genes are not properly activated.“This disorganisation within the cell’s nucleus results in a neuron that doesn’t perform very well — like a car running on five cylinders instead of six,” he said.The cerebellum contains roughly half the neurons found in the brain. It also develops in response to external stimuli.So, as we practice tasks, certain genes or groups of genes are turned on and off, which strengthens these circuits and helps to stabilise or perfect the task being undertaken.

The researchers found that the Snf2h gene orchestrates this complex and ongoing process. These master genes, which adapt to external cues to adjust the genes they turn on and off, are known as epigenetic regulators.

“These epigenetic regulators are known to affect memory, behaviour and learning,” said Picketts.

“Without Snf2h, not enough cerebellar neurons are produced, and the ones that are produced do not respond and adapt as well to external signals.“They also show a progressively disorganised gene expression profile that results in cerebellar ataxia and the premature death of the animal,” he said.

The study was published in the journal Nature Communications.