TDP-43 Depletion as a Risk Factor Promoting Tauopathy in AD

Resham Chhabra, PhD Johns Hopkins University


Tong Li, PhD Johns Hopkins School of Medicine
Philip Wong, PhD Johns Hopkins School of Medicine


My research aims to determine whether depletion of TAR DNA-binding protein 43 (TDP-43) in neurons contributes to pathological conversion of tau or accelerates tauopathy, a critical driver of neuron loss and cognitive decline in sporadic Alzheimer’s disease (AD). The pathological alteration and aggregation of tau protein (called tauopathy) is arguably the most important alteration in AD, as it shows the strongest association with the loss of brain cells and memory. Many studies have shown TDP-43 abnormality in 30-70% of AD cases, and that these cases show worsened memory loss. The aim of our study is to find out if TDP-43 loss plays a role in the initiation or acceleration of tauopathy in AD. Once we know what drives the changes in tau, we can halt or slow the progression of this disease. 

Project Details

In addition to amyloid plaques and tau tangles, which are the two pathological hallmarks that define AD, a TDP-43 abnormality has been reported to contribute to the worsening of memory in a subset of AD patients.  Studies support the idea that TDP-43 loss may indeed be a main culprit, and that loss of TDP-43’s ability to function within the nuclear compartment of nerve cells could be a risk factor influencing the alteration of the tau protein in AD brains.  It is thought that clumping of the tau protein into aggregates underlies the loss of nerve cells and ensuing memory deficits. To test whether loss of this TDP-43 protein would serve as a risk factor, we will take advantage of our newly developed AD mouse model that facilitates the clumping of normal tau protein in the presence of amyloid plaques. The results of our study will lead us to establish that TDP-43 loss is a risk factor by influencing the clumping of the tau protein. These results will point to development of drugs to halt or slow the progression of this devastating disease.