Project Details
Description
Alzheimer’s disease (AD) and many related dementias (ADRDs) are tauopathies, characterized by
somatodendritic accumulation of tau and intraneuronal inclusion bodies composed of tau species that have
undergone extensive post translational modification. Although some disease-specific Tau modifications have
been identified, many are conserved across the full range of tauopathies. We do not yet have a deep
understanding of the molecular processes that generate these tau protein modifications, or of their functional
consequences in promoting pathogenic cascades. This knowledge gap is a major contributor to our current
inability to generate effective therapeutic interventions for AD and other tauopathies. The central hypothesis we
are testing here is that a range of pathogenic events induce phosphorylation of tau at specific residues, resulting
in mislocalization of tau within the cell and subsequent synaptic dysfunctions, and that inhibition of these early
tau phosphorylation events will in turn inhibit tau pathologies and associated signaling deficits. This hypothesis
is based on our published work, primarily utilizing cultured cell experimental systems. The direct relevance of
this mechanism to human disease is further supported by the recent finding that phosphorylation of tau at these
same specific residues is an early event preceding tau fibril formation in AD disease progression. Our overall
objective here is to test and further refine this hypothesis in a novel mouse model we have developed (MAPT-
GR) that expresses all isoforms of human tau at physiologic levels and ratios. We have found that mild traumatic
brain injury (mTBI) induces a rapid phosphorylation and somatodendritic mislocalization of the human tau in
these mice. Importantly, we can prevent this tau mislocalization by inhibiting phosphorylation. The specific aims
are to: 1. Determine the dynamic changes in the subcellular distribution of phosphorylated tau. We will
utilize our novel tauopathy model to test the working hypothesis that phosphorylation of tau at specific residues
leads to somatodendritic accumulation of tau, tau mislocalization to dendritic spines, and alters micro-
components of dendritic spines. 2. Determine the synaptic and circuit dysfunctions associated with the
phosphorylation of tau. We will test the working hypothesis that mislocalization of phosphorylated tau to
somatodendritic domains and dendritic spines results in synaptic and circuit dysfunction in our model. 3. Identify
the impact of inhibiting these early phosphorylation events on tau mislocalization and associated
signaling deficits. We will test our working hypothesis that mTBI activates GSK3β and CDK5, which
phosphorylate the B and C domain of the tau protein. Expected Outcomes: We expect to identify the early-stage
pathologies and dysfunctions caused by phosphorylation of tau and provide proof-of-concept demonstrations of
the extent to which these dysfunctions can be prevented by blocking tau phosphorylation at specific residues.
Of equal importance, we expect to have optimized a model and experimental platform in which potential
therapeutic compounds that target this common disease mechanism can be tested and optimized.
Status | Active |
---|---|
Effective start/end date | 6/1/22 → 2/28/25 |
Funding
- National Institute on Aging: $767,250.00
- National Institute on Aging: $767,250.00
- National Institute on Aging: $690,526.00
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