Vision statement: Linking tau proteostasis with neuronal activity in frontotemporal dementia

Tauopathy is a prevalent and devastating neurodegenerative condition in the elderly. Tauopathies include Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), a major subtype of FTLD characterized by changes in behavior, difficulty with language, and problems with body movement. Tauopathies are untreatable. A better understanding of their pathogenesis is urgently needed to develop novel treatments.

Tauopathy is characterized by the accumulation and spread of pathogenic forms, key features of imbalances in tau levels. Thus, how tau becomes imbalanced and the functional outcome of such an imbalance are at the core of tau pathogenesis. West cWOW scientists hypothesize that there is a connection between tau imbalance and neuronal dysfunction. Understanding this connection would shed new insights into mechanisms underlying tau pathogenesis.

The center’s researchers aim to address three fundamental questions:

  1. What causes tau to accumulate and spread in FTD?
    Accumulation of tau inside cells, as well as spreading between cells, are two interconnected key features of tau imbalance. For tau accumulation, the scientists will address the role of tau mutations and tau fibrils using a combination of proteomic, transcriptomic, and hypothesis-driven approaches. For tau spread, they will systematically analyze the mechanisms underlying the following processes: release, uptake, and seeding (uptake that alters endogenous tau).

  2. How does imbalanced tau levels induce neuronal dysfunction in FTD?
    Although insoluble tau is often the hallmark of tauopathy, soluble tau (e.g. those that are improperly modified) could also be important in inducing neuronal dysfunction. The center will address the functional toxicity of both soluble tau and insoluble tau fibrils using a combination of traditional electrophysiology recordings and multi-electrode array for network activities.

  3. How does neuronal activity modulate tau imbalance in FTD?
    Both in vitro and in vivo studies showed that the release of tau is activity-dependent. The aberrant neuronal activity could serve as a feedback loop, further amplifying the tau imbalances in FTD. The scientists will test this hypothesis using innovative approaches that combine proteomic/transcriptome analyses with neuronal activity modulation.