Tau Protein: 45 to 60 kD protein found in neurons; plays a key role in microtubule stabilization and neuronal structure.
Normal function includes:
Involvement in tubulin assembly.
Production and stabilization of microtubules.
Contribution to neural morphology and axonal growth.
Tau Pathology in Alzheimer's Disease
Abnormal Tau: In Alzheimer's, tau becomes hyperphosphorylated and forms tangles, leading to dysfunctional microtubules.
Tau undergoes conformational changes, initially observed by Braak and Braak, resulting in an abnormal build-up of tau in neurons.
Tangles: Neurofibrillary tangles (NFTs) form from tau; associated with neurotic plaques surrounding beta-amyloid cores, indicating advanced Alzheimer's pathology.
Hyperphosphorylation: A key process leading to tau dysfunction. Normal phosphorylation by kinases is disrupted, resulting in destabilizing tau's function and facilitating aggregation.
Progressive Staging of Alzheimer's Disease
Progression: Starting in the entorhinal cortex, tau pathology progresses to hippocampus, temporal cortex, and eventually the motor cortex as the disease advances.
The spread of tau correlates with the severity of cognitive symptoms, emphasizing tau as a significant pathological marker.
Current Research Model by T-Rex Therapeutics
Novel Tau Model:
Infusion of human tau into rat hippocampal neurons to investigate the impact of tau hyperphosphorylation on cognitive function.
Delivery Method: Utilization of polymeric nanoparticles (polyps) to introduce tau directly without crossing the blood-brain barrier.
Experimental Methods and Findings
Phosphorylation Induction: Using oxidized acid to induce tau hyperphosphorylation, observed effects on cognitive impairment and synaptic transmission via water maze tasks and long-term potentiation (LTP) assessments.
Control Groups:
Animals receiving only polyps showed no significant cognitive impairment.
Tau delivered without hyperphosphorylation resulted in minor deficits compared to those with hyperphosphorylated tau, which exhibited significant cognitive impairment.
Pathological Confirmation
Tissue Analysis: Post-experiment staining for tau reveals significant levels of phosphorylated tau only in the group receiving oxidation, confirming the model's relevance to pathology observed in actual Alzheimer's patients.
Conclusion and Future Directions
Conclusions: Initial findings demonstrate the feasibility of using this model to mimic Alzheimer’s-related tau pathology and its effects.
Hyperphosphorylation is crucial in inducing cognitive deficits relevant to Alzheimer's pathology.
Future directions include improving the model to assess various aspects of Alzheimer's, considering complex interactions (cholinergic, tau, amyloid).
Therapeutic Targets: Focus on preventing tau and amyloid protein aggregation to delay disease progression.
Importance of enhancing understanding through preclinical models to aid in developing new treatments for Alzheimer's.