Tau-independent Microtubule Defects in Alzheimer’s: Potential New Drug Targets
Alzheimer's disease (AD) is the most common cause of dementia and the sixth leading cause of death in the United States. It is critical that we find new therapies to prevent and treat AD. The experiments in this proposal are designed to find new pathways by which toxic forms of beta amyloid (Aβ), a peptide associated with AD, damages microtubules, tube-like structures used to move components around in cells, including neurons in the brain. Typically, damage to microtubules is blamed on abnormal tau formations in the Alzheimer’s brain, but we plan to test the novel hypothesis that Aβ has neurodegenerative effects independent of tau that affect microtubule stability, and that microtubule stabilizing agents can protect neurons against Aβ neurotoxicity. New drugs will be tested to determine if they can reverse some of the detrimental effects of Aβ accumulation in the brain.
We are helping to generate new treatments for AD by researching how cellular defects arise and developing strategies to prevent or reverse them. Our specific interest lies with microtubules, tube-like structures used to move components around in cells. Normal tau protein helps maintain the structure of microtubules, but this is disrupted in AD. However, our focus is not on tau, but on other pathways to microtubule damage, including the role of toxic Aβ. We are testing the novel hypothesis that Aβ has neurodegenerative effects independent of tau and that microtubule stabilizing agents can help protect neurons against Aβ neurotoxicity.
The first part of my project aims to determine how it is that Aβ damages neurons, and whether the pathways involved in causing this damage in AD are distinct from tau-dependent pathways. We are studying these problems both in neurons cultured in dishes, as well as in mouse models of AD.
The other major component of my research involves testing various drugs and compounds for their ability to restore the function of neurons damaged by beta amyloid. The current understanding in the AD field is that the effects of toxic Aβ depend on the presence of tau, and most current treatment strategies are contingent on this. However, we believe that Aβ has effects that can be treated even before tau pathology is present. We are testing specific drugs that block cell channels that we believe get activated in the presence of Aβ. For the first time, our research will test the feasibility of these channel blockers as AD drugs to rescue cells from Aβ-induced microtubule disruption and dystrophic neurite formation. If we are successfully able to reverse the effects of Aβ using that treatment strategy, it would open up a whole new avenue of drug development in AD. In addition, the field would gain tremendous knowledge from our better understanding of the relationship between Aβ, tau, and AD progression.
About the Researcher
I am a postdoctoral research fellow at Northwestern University in the laboratory of Dr. Robert Vassar, where I study the role of Aβ in causing neuron degeneration and dysfunction in Alzheimer’s. My PhD research was done at Columbia University under the supervision of Dr. Richard Vallee, where I studied motor protein regulation during brain development. Prior to graduate school, I was a research assistant to Dr. Sanford Simon at The Rockefeller University, where I was involved in projects related to endocytosis and vesicle trafficking. I received my bachelor’s degree from Mt. Holyoke College, where I also carried out independent research on protein folding in the laboratory of Dr. Sean Decatur. I aim to utilize my background in structural biology, cell biology, and neuroscience to address research questions in AD. I also have an interest in science education and communication and plan to pursue an academic research career involving teaching.
The human brain is one of the least understood organs of the human body. Diseases that affect the brain are therefore all the more devastating, because we are still developing our understanding of how the brain works and do not have the necessary tools to treat such diseases. Compounded with the effects of aging, neurodegeneration wreaks havoc on the brain, the mind, and the ability to retain the “self”, which is essentially what makes us who we are. I witnessed this firsthand when my grandmother’s Parkinson’s got progressively worse. At the time, I was a graduate student in NYC, and my family was quite far in Pakistan and the UK. My grandmother’s transition from a vibrant, active woman to a person trapped by the degeneration of her neurons was all the more shocking to me, since I only saw her at most once a year when I would visit over the holidays. My graduate field of research was in brain development, and I struggled to understand how neurodevelopmental processes that are so active during growth and development must be so drastically reversed during aging, and are unable to cope with the loss of neurodegeneration. In diseases like Parkinson’s and Alzheimer’s, once robust cellular processes such as axon elongation, trafficking, and protein degradation slow down till the cell is no longer able to function as it once did. As a field, we are still trying to understand the complexities of what makes the cells in our brains so vulnerable as we get older. I dedicated my graduate thesis to my grandmother, who passed away two weeks before I defended. Her disease had some influence on my research interests, and for my postdoctoral work, I have chosen to pursue neurodegeneration in the context of Alzheimer’s disease. Small advances at the bench lead me to believe that eventually, new therapies and possibly even a cure for Alzheimer’s lie in our not-so-distant future. I continue to be inspired by other scientists, my labmates, and my mentor, all of whom are passionate about finding a cure for Alzheimer’s. Above all, I am inspired by those directly affected by Alzheimer’s and other brain disorders – the patients and caregivers that encounter the disease and deal with it on a daily basis. I am incredibly grateful for the financial support provided by BrightFocus donors, which is allowing me to pursue novel lines of inquiry in my research and hopefully make an impactful contribution to the field.
First published on: July 26, 2017
Last modified on: June 30, 2019