Our Research

​Understanding the Pathophysiology of Tau in Alzheimer's disease and related dementia

Alzheimer’s disease (AD) and other tauopathies such as frontotemporal lobar degeneration with tau inclusions (FTLD-tau), are the most prevalent neurodegenerative diseases in the US and worldwide. In tauopathy brains, tau protein accumulates and aggregates into fibrillary tangles, the pathological hallmark of the disease. Toxic tau not only accumulate in neurons, but also spread from one to the other, which correlates with progressive cognitive decline and neurodegeneration. Understanding the proteostasis and pathophysiology of tau is critical for devising new therapeutic strategies.

We ask three fundamental questions:

  • What makes tau a toxic protein in the diseased brain?

  • How does pathogenic tau form and accumulate in neurons?

  • ​How does tau spread from neurons to neurons? 

Intriguingly, tauopathies are strongly associated with metabolic deficits. Tau accumulation coincides with areas of glucose hypometabolism, together with alterations in the brain metabolic profile. Metabolic disorders, such as diabetes, increase the risk for AD. Hence, there is a growing interest in treating AD via metabolic modulation. While the neurodegeneration and metabolic dysregulation are phenotypically linked, the molecular mechanisms remain elusive. One of our long-term goals is to decipher the molecular basis for how metabolic dysregulation modulates neurodegeneration. Specifically, we hope to answer these key questions:

  • What signaling pathways underlie metabolic dysregulation in tauopathy brains?

  • Does aberrant metabolism exacerbate neurodegeneration? If so, how?

  • Are there cross-talks between metabolism and other biological process, such as inflammation, hormone, circadian, that could modulate the pathophysiology of tau?

Answering these questions is critical for understanding the reciprocal regulation of metabolism and neurodegeneration, thereby setting the groundwork for devising novel strategies to treat these deadly diseases.

We are armed with cutting-edge techniques and model systems including Drosophila, mouse and cell culture (primary neuron/microglia and iPSC-induced neurons).

 

We take both candidate approach and systematic approach to uncover new regulatory mechanisms bridging metabolism and tau pathogenesis. 

 

In the future, we will explore therapies to target these mechanisms by pre-clinical studies. 

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© 2020 by Xu Chen Lab @ UCSD