Bio Patrika interviews Dr. Kedia on his thoughts about “Role of synaptic nanoscale organization in Alzheimer’s disease”

Dr. Shekhar Kedia’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dr. Kedia is Postdoctoral fellow in the lab of Dr. Deepak Nair at Centre for Neuroscience, Indian Institute of Science (IISc), Bangalore, India. Dr. Kedia published a paper titled “Alteration in synaptic nanoscale organization dictates amyloidogenic processing in Alzheimer’s disease” in iScience (2020) as a first author.

How would you explain your paper’s key results to the non-scientific community?

Neurons are the fundamental building blocks of the brain. Synapses are connections that dictate the efficiency of the flow of information between neurons transmitting a signal from the presynaptic neuron to the postsynaptic counterpart (Fig. 1). The alterations in the molecular makeup of the synapses are implicated in a variety of diseases. It is also believed to affect higher cognitive abilities, like learning and memory. Neurodegenerative diseases like Alzheimer’s disease (AD) are postulated to begin as a synaptopathy, i.e., illness of synapses. In AD, peptides called Amyloid beta (Aβ) are deposited in several brain regions, leading to memory loss. Aβ is derived by the breakdown of a protein called Amyloid Precursor Protein (APP) by the sequential action of enzymes called Secretases through the amyloidogenic pathway.

Figure 1. A schematic of the synapse depicting components of amyloidogenic machinery i.e., APP and Secretase organization at synapse in nanoscale. APP and Secretase monomers and nanodomains are also shown. Molecules shown are not scaled.

Our study showed how the major components of the amyloidogenic machinery namely, APP and secretases are organized at the level of synapses at the nanoscale (Fig.1). Using state-of-the-art super-resolution microscopy techniques allows us to visualize these molecules at synapses with a spatial resolution of few tens of nanometers. We found that APP and Secretases are organized into nanoscale clusters called as “Nanodomains” (Fig. 1, 2). We further demonstrated that this organization is different between functional compartments of the synapse and changes in such an organization contribute to the onset of AD. In simpler terms, we investigated the role of slow-moving, densely populated APP clusters (“sitting duck”) and rapidly diffusing, APP monomers (“movers and shakers”) as being advantageous to produce detrimental peptides and discovered that this production increases with a higher number of confined APP or Secretases molecules inside a nanodomain in a simulated vesicle. It was validated in multiple models of AD like brain slices from mice models and human brain slices from neuropathologically confirmed AD patients.

Figure 2. A bird’s eye view of the synapse showing the nanoscale organization of APP and Secretases (β- and γ-secretases) in the post- and perisynaptic functional zones of the synapse.

“[…] results highlight a new way of regulating the toxic products formed through the amyloidogenic pathway, providing a new dimension to AD therapeutics.”

What are the possible consequences of these findings for your research area?

To the best of our knowledge, we demonstrate for the first time how nanoscale alterations in the molecular fingerprints of the amyloidogenic machinery lead to long-term deficits, as seen in AD. These findings open an entirely new avenue for designing early intervention therapeutic targets for AD. Nanoscale smart probes targeting the chemical composition of APP or Secretases nanodomains could be the focus for next-generation therapeutic strategies. Therefore, these results highlight a new way of regulating the toxic products formed through the amyloidogenic pathway, providing a new dimension to AD therapeutics.

What was the exciting moment (eureka moment) during your research?

The best moment in research is when the “predictions” obtained through in silico simulations are validated experimentally. The “eureka” moment for me was when we found that nanoscale compositionality of APP and secretases are altered in brain slices obtained from both mice and humans. These results reinforced our mathematical simulations. It was exciting to see the investigations in human brain slices falling in line with mathematical predictions.

What do you hope to do next?

I want to continue exploring Alzheimer’s disease nanobiology. I firmly believe that interdisciplinary research is crucial to understand AD better and develop newer therapeutics. In this context, I intend to explore AD therapeutics with interdisciplinary research spanning several disciplines like nanoscience, neuroscience, and materials science. My future interests are designing smart nanomaterials that can cross the blood-brain barrier to modulate the nanoscale organization of the multiple components of the amyloidogenic machinery.

Where do you seek scientific inspiration?

As a kid, I was always fascinated by the diversity of nature around me, especially flora and fauna. It led to a natural inclination for the biological sciences. The beauty and diversity of nature fascinate me a lot and drives my curiosity. Moreover, till now, we do not have an effective cure for Alzheimer’s disease. Most of the drugs available in the market only provide symptomatic relief from AD. It is hard to see the sufferings of the AD patients. It gives me a tremendous amount of motivation to work for the betterment of human life and society by performing research directed towards AD biology and therapeutics. I hope I would be able to contribute in this direction by working at the interface of science and society.

How do you intend to help Indian science improve?

I think that it is essential for scientists to have a cross-talk with society. I would like to see more initiatives like “BioPatrika” where scientists can communicate with society. It helps to bridge the gap between the two. It creates awareness among people about the usefulness of science to society. I hope to create more awareness about Alzheimer’s disease through science communication in my little way.

Further, the kind of work I did in my PhD was once possible only outside India. I would like to strongly emphasize that Indian science has developed a lot and is continuously improving and becoming at par with developed countries. I hope this message inspires more and more students to stay in India and contribute in their small way towards the welfare of our society.

Reference

Kedia S, Ramakrishna P, Netrakanti P R, Singh N, Sisodia S S, Jose M, Kumar S, Mahadevan A, Ramanan N, Nadkarni S, Nair D. Alteration in synaptic nanoscale organization dictates amyloidogenic processing in Alzheimer’s disease. iScience (2021); 24: 101924.

Author introduction and research interests

I am currently working as a bridging postdoctoral fellow at Dr. Deepak Nair’s laboratory at Centre for Neuroscience, Indian Institute of Science, Bangalore, India. I completed my PhD in Neuroscience from the same laboratory. I am trying to understand the nanobiology of Alzheimer’s disease, particularly the nanoscale organization of APP and secretases at the level of synapses using super resolution microscopy techniques. These investigations might help us to better appreciate the contribution of nanoscale deficits in the onset of Alzheimer’s disease, leading to the development of novel early intervention strategies.

Email: shekhar@iisc.ac.in

Read more about Dr. Deepak Nair lab research interests here: http://www.cns.iisc.ac.in/deepak/index.html

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