Alzheimer’s disease is one of the most devastating ailments amongst all neurodegenerative disorders; accounting for about 70-80% of all dementia globally [1].
Estimates say that more than 44 million people around the world, developed nations and otherwise, have the illness although merely one in four is diagnosed. The number of cases is predicted to rise further, to 135 million, by 2050 [2] (Figure 1). These are staggering numbers by themselves, but recent projections paint an even grimmer picture. It is predicted that the number of patients with Alzheimer’s disease (AD) will increase rapidly in the next few years and that it may soon become the leading cause of death the world over, overtaking ischemic heart disease, brain stroke, acquired immune deficiency syndrome (AIDS) and cancer [3,4] (Figure 2). AD in its most severe form also involves significant caregiving cost. Add to that a lack of approved early-diagnosis method and no effective clinical options for treatment, and you have a rightful cause for alarm.
From Visually.
AD as an illness is notoriously difficult to pin down, for both diagnosis and therapy, because of the multiple ways it can affect a healthy neuron. Current AD diagnosis is traditional – still based on behavioral or cognition tests in patients. Any observation of symptoms indicates an already advanced stage of AD, impossible to prevent or treat. Moreover, AD caused dementia often coexists with other dementia-types, including Picks disease, Parkinson’s disease-related dementia and others, in a condition referred to as mixed dementia or dementia-multifactorial. Arming clinicians with the right tool to distinguish between these different coexisting dementia types could thus be an important factor in developing and providing early AD treatment.
AD, simply put, is caused by plaque deposition in the brain. One of the major constituents of this plaque is the amyloid protein, which gets misfolded and deposited as plaque. Recent studies have shown that amyloid deposits and early symptoms of the disease develop decades before the visibly detectable decline in cognitive behaviour. Interestingly, plaque formation in the brain can also be due to an abnormal, chemical transformation of the microtubule-associated ‘Tau’ protein of an otherwise healthy neuron. The ‘Tau’ protein controls transport of biomolecules within the neuronal cell. A transformed ‘Tau’ results in microtubules forming tangles within the neuron, called neurofibrillary tangles (NFT). NFT and plaque formation together is a deadly combination – adversely affecting a large number of vital pathways and throwing a healthy neuron totally out of gear. NFT and plaque are responsible for oxidative stress, inflammation, membrane toxicity, biomolecular and mitochondrial damage, all micro level problems that show up at the cellular or macro level as DNA and protein damage, damaged lipid metabolism and intracellular signalling, disrupted autophagy regulation, neurotransmitter release and synaptic function; ultimately resulting in neuronal death.
NFT alone, however, is a signature of tauopathy, a term coined by neuroscientists to indicate the breakdown of the normal Tau-protein functionality. Tauopathy is responsible for causing dementia across the board, not just AD. Differential diagnosis of AD against other neurodegenerative diseases thus calls for concentrating on the other factor in plaque formation — amyloid production and its aggregation. A research group at Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), led by Dr. T Govindaraju, is devising this very tool using a molecular probe that will respond to Positron Emission Tomography (PET) tests.
More specifically, Dr. T. Govindaraju and his team are developing molecular tools for in vitro, and in vivo fluorescence, and positron emission tomography (PET) imaging of brain tissue, blood, and cerebrospinal fluid (CSF) samples that can capture the formation of amyloid plaque while not binding to NFT caused by Tau-protein or aggregates of proteins responsible for other neurodegenerative disorders such as Parkinson’s disease etc. These molecular tools are aimed at aiding early diagnosis, studying various stages of disease progression, and also offering ways to develop novel therapeutic agents for the currently incurable AD. Early detection after all will be a major achievement!
The Govindaraju group has developed a unique probe, CQ, which shows very high selectivity for amyloid plaques in Near-Infrared (NIR) range. CQ has been tested in the lab already for in vitro detection in ailing blood, CSF and brain tissue where it has shown extremely encouraging results against the commercially available probes thioflavin (ThT) and Congo Red [5]. CQ’s switch-on NIR fluorescence is so bright and selective that even shining an ordinary green laser pointer at a tube containing a solution of CQ and amyloid protein aggregates results in the beam turning red inside the tube. Its ability to cross blood-brain-barrier and non-toxicity to neuronal cells all point towards it being a reliable probe even for in vivo imaging. But what surprised the group was CQ’s amyloid ‘smartness’ or rather its highly selective amyloid-aggregate binding, even in the presence of Tau aggregates or NFTs. The work, thus, has clear implications for diagnosing early AD differentially against tauopathies and other neurodegenerative diseases even in mixed-dementia cases where traditional diagnosis methods fall short.
However, Dr. Govindaraju said at an interview at JNCASR, ‘At this stage CQ is useful for academic, medical or disease research, and in vivo imaging of animal models only. CQ crosses blood-brain barrier and is non-toxic to humans as well, but in vivo fluorescence imaging of the human brain is limited by the current scope of fluorescence imaging techniques. So CQ is not yet a viable diagnostic tool’. So what’s next for the team? A Positron Emission Tomography or PET-capable probe, with the introduction of just a single radioactive tracer atom in its structure, is the answer. Such a probe could open up AD-detection specialized PET scanners even for in vivo imaging. The group is currently substituting CQ with the right radioactive atom that has a low enough halflife so as to be non-toxic and yet high enough to allow for optimal PET imaging and viewing. Dr. Govindaraju says “this PET-capable probe, once ready, will go into a clinical diagnostic kit”. Such a ‘smart’ PET-capable probe can potentially turn current AD detection statistics on its head.
Apart from CQ, the group is also designing other probes that latch on to AD’s multifactorial toxicity as potential disease markers. They have already developed NIR probes that can assess biometal levels and oxidative stress through tracking reactive oxygen species (ROS) in brain tissue; both of which play key roles in triggering AD [6]. Most of these NIR probes have been patented nationally and internationally, and could be a part of a future composite AD tool kit that can target AD’s multifactorial nature. Their startup company, VNIR Biotechnologies Pvt. Ltd. plans to make the probes available in the market for academic and disease research very soon.
The story does not end at diagnosis alone for Dr. Govindaraju and his team. In their recent work on AD therapy, they are targeting AD’s multifactorial neuronal toxicity through unique multifunctional drug candidates that block multiple disease pathways [7]. Their search for such ‘smart’ drug candidates with multifunctional firefighting abilities has led them to two very promising candidates, one synthetic and another natural product-derived. Both compounds are undergoing tests in transgenic mice with AD. With extremely encouraging preliminary results on mice, “there may be light at the end of the tunnel.” says Dr. Raju.
Neurons are irreplaceable. It is well known in literature that the human brain does not generate neurons beyond a certain age [8]. Scientists however, have been optimistic about neurogeneration using neuronal stem cell therapy as a stop-gap AD cure. Dr. Raju and his team too have harnessed this concept by designing a novel silk-based biomimetic compound as a trigger for neurogeneration in a very specialized form of neuronal stem cell therapy. “This work along with the earlier two ‘smart’ drugs could provide clinical options for a holistic AD treatment very soon.” remarks Dr. Raju and “help me achieve my research dream of devising both diagnostics and treatment options for AD”, he signs off.
References
1. Alzheimer’s & Dementia 2015, 11, 332. ; Chem. Commun. 2015, 51, 13434
2. Alzheimer’s & Dementia 2015, 11, 332; https://visual.ly/community/infographic/health/dementia-global-epidemic
3. M. Prince, R. Bryce, E. Albanese, A. Wimo, W. Ribeiro, and C. P. Ferri, Alzheimer’s & Dementia 2013, 9, 63.
4. A. Ciechanover and Y. T. Kwon, Exp. Mol. Med. 2015, 47, e147.
5. Biosens. Bioelectron. 2017, 98, 54-61; Sci. Rep. 2016,
6. 23668 6. Chem. Sci. 2016, 7, 2832; Nucleic Acids Res. 2015, 43, 8651-8663; Org. Biomol. Chem. 2013, 11, 2098
7. Chem. Commun. 2015, 51, 13434
8. https://www.theguardian.com/science/neurophilosophy/2012/feb/23/brain-new-cells-adult-neurogenesis
The article was updated on April 14, 2018 to correct the statement ‘At this stage CQ is useful for academic and medical or disease research only. Due to possible toxicity of the dye, in vivo fluorescence studies are not the kind of diagnostic tool clinicians would want to buy’.
About the author
Debarshini Chakraborty is an erstwhile scientist with a deep passion for science communication, science policy and outreach- a person of many hats. Science, to her, is a way of thinking. Trained in theoretical soft condensed matter physics, through the years she has branched out in various directions away from pure academia although it’s always a scientist’s hat that goes on when she brings in her own spin to her work. Currently, her professional interests lie in science communication, policy and project specific strategic communication. Having worked in unusual roles in multiple research institutes, in an embassy science department and now in a bio startup incubator, Debarshini feels that strength in targeted communication requires command over both science and language, subject and matter. Debarshini is open to connecting with anyone who shares the same career goals on Facebook and LinkedIn.
Editors
Arunima Singh, obtained her PhD from the University of Georgia, and is currently a postdoctoral researcher at the New York University. A computational structural biologist by training, she enjoys traveling, reading, and the process of mastering new cuisines in her spare time. Her motivation to move to New York was to be a part of this rich scientific, cultural, and social hub.
Illustrators
Saurabh Gayali recently completed his Ph.D. in Plant Molecular Biology from National Institute of Plant Genome Research (JNU), New Delhi. He is currently working in the same lab in projects involving the study of abiotic stress response in crop plants apart from actively seeking the post-doctoral position. He has a keen interest in data analysis, visualization and database management. He is skilled 2D and 3D designer with a specific interest in scientific illustration. In leisure, Saurabh plays guitar and compose music, does photography or practice programming. Follow him on Instagram
Disha Chauhan did her Ph.D. in IRBLLEIDA, University of Lleida, Spain in Molecular and Developmental Neurobiology. She has post-doctoral experience in Cell Biology of Neurodegenerative diseases and is actively seeking a challenging research position in academia/industry. Apart from Developmental Neurobiology, she is also interested in Oncology. She is passionate about visual art (Illustration, painting, and photography) and storytelling through it. She enjoys reading, traveling, hiking and is also dedicated to raising scientific awareness about Cancer. Follow her on Instagram
Blog design: Arunima Singh
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