Acad 2011

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Fight against loss of intellectual ability

What do people fear most? When do they rush to a doctor? Apparently, the greatest fear is death, followed by Alzheimer's disease. This disease is named after a German physician Alois Alzheimer (1864-1915). This disease is associated with general shrinkage of the brain tissue with deposits of amyloid – β protein (Cholinergic neurons) and abnormal filaments composed of tau protein in the brain that include a loss in the activity of cholinergic neurons. Some inherited forms are associated with genetic locus on chromosome 21. Amyloid tissue is consisting of protein fibrils that may accumulate between cells in various animal tissues, especially in the disorder of amyloidosis. Amyloid deposits are insoluble and can exert pressure on various vital organs. These deposits are generally detected by staining with dye Congo red. A build up of amyloid tissue in the brain is a feature of Alzheimer's disease.

Accumulation of the amyloid – β in the brain is a hallmark of Alzheimer's disease (1). It is generated from amyloid precursor protein by consecutive cleavage events that involve the presenilin enzyme complex. So why not target this complex for treating this disease? The problem is that, this enzyme complex act on several other proteins that are crucial for health and will also be affected by its inhibition. He et al (2) described a protein called γ-secretase activating protein (GSAP) and they showed that its depletion selectively prevents amyloid – β production by the presenilin complex. The γ – secretase is a protease with numerous substrates. Little is known about the molecular mechanism that confers substrate specificity on this potentially promiscuous enzyme. The presenilin complex consists of four core proteins:

PS1 / PS2 , APH-1, nicastrin and PEN-2 (3,4). In addition to amyloid precursor protein (APP), other notable substrates of this complex include Notch and N-Cadherin proteins, which span the cell membrane. The complex cleaves these proteins at amino acid residues within their transmembrane domain.

GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP simulates amyloid – β production in vitro. Reducing GSAP concentration in cell lines decreases amyloid – β concentration.

Knockdown of GSAP in a mouse model of Alzheimer's disease reduces levels of amyloid –β plaque development. GSAP represents a type of γ-secretase regulator that directs enzyme specificity by interacting with a specific substrate (2). He et al (2), demonstrated that imatinib (Gleevec), an anti cancer drug previously found to inhibit amyloid-β formation without affecting Notch cleavage (5), achieves its amyloid – β lowering effect by preventing GSAP interaction with the γ-secretase substrate, amyloid precursor protein carboxy-terminal fragment (APP-CTF). Thus GSAP can serve as an amyloid -  β lowering therapeutic target without affecting other key functions of γ-secretase (2). Presenilin proteins have a major role in normal cellular processes, but some contribute to disease, for example through the formation of amyloid – β. The way in which these different roles are regulated is now becoming clearer.

Diagnosis :

The US Food and Drug Administration (FDA) usually follow advice from its advisory committees, and Alzheimer's experts anticipated that the brain scan would be approved. FDA recommended unanimously on 21st January 2011 that the agency approved the first test – a brain scan – that can show the characteristic plaques of Alzheimer's disease in the brain of a living person. The approval hinged on radiologists agreeing on what the scan says and doctors being trained in how to read the scan. Plaques are part of the criteria for having Alzheimer's – if a person with memory problems does not have plaques, that person does not have Alzheimer's. But without the scan, the only way to know if plaques are present is to do an autopsy.

This positron emission tomography (PET) scan is like a non-invasive biopsy of the brain – it can give a specific diagnosis of Alzeimer's in the early stages of the disease. The additional requirement, would not be a big hurdle, said Dr. D. M. Skovronsky, chief executive of the company, Avid Radio pharmaceuticals, that applied to market the scans. Dr. P.N. Tariot, director of the memory disorder centre at the Banner Alzheimer's institute in Phoenix, Arizona said that this is a big deal. He is an investigator in studies at Avid, now a subsidiary of Eli Lilly and company, and its competitors.

The approval would be for a dye that homes in on plaque in the brain, making it visible on PET scan. Such scans would be especially valuable in a common and troubling situation – trying to make a diagnosis when it is not clear.  Whether a patient's memory problems are a result of Alzheimer's disease or something else. If a scan shows no plaque, the problems are not caused by Alzheimer's and could be from tiny strokes.

In 2008, an advisory committee to the FDA said that in order for the dye to be approved for amyloid imaging, the company would have to show that the scans were detecting the same plaques as were found on autopsy. Avid did that, using people at the end of life who agreed to be scanned and then to have brain autopsy. The company also tested young healthy people who, presumably, would not have amyloid plaque in their brains.

Alzheimer's specialist said that if the scans were approved it would come into wide spread use. This is the reason why people rush to neurologist when anything goes wrong with their brains.

Reference: 

1. Salkoe, D.J. Alzheimer's disease : genes, protein and therapy. Physiol. Rev. 81, 741-766 (2001)


2. He. G et al. Nature. 467,95-98 (2010)


3. Sherrington. R. et al. Nature, 375, 754-760 (1995).


4. Francis. R. et al. Dev. Cell. 3, 85-97, (2002)


5. Netzer. W. et al. Proc. Natl. Acad. Sci.USA, 100, 12444-12449 (2003).

About the Author

I was born in Kolkata, Qualified Ph.D on 1989 from Calcutta University (Spl. Endocrinology), acquired research experience of more than 22 years with publications of around 29 papers in various national / international journals , acquired teaching experience of more than 15 years, acquired experience of writing biology text book under ISC course which is currently under Cambridge press (Kolkata) for publication. Awarded Sangit Prabhakar and Prayag Sangit Samiti in Indian Classical music.  Awarded certificate of appreciation – Celebrations of the centenary of Ramkrishna Mission & of Swamy Vivekananda's historic return from west in 1897 as well as of 66th foundation day of the pratisthan.  Ramakrishna Mission Seva Pratisthan (Kol-India), expressed its participation of my contribution to the success of the seminar in 1997. 

Overview of New Features — AutoCAD 2011


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