One of the most fundamental and unresolved questions in the Alzheimer's disease (AD) field is whether therapies aimed at clearing Abeta will suffice to stop the progression of this insidious disease. In other words, will removing Abeta plaques impact the subsequent development of AD neuropathology, including the progression of the neurofibrillary pathology? This question, to date, has been intractable in humans. Because my lab developed the first transgenic mouse model (herein referred to as the 3xTg-AD mice) in which both amyloid plaques and neurofibrillary pathology develop in AD-relevant brain regions, in a progressive and age-related fashion, we are uniquely positioned to determine whether treatments targeted specifically at Abeta can also ameliorate the tau pathology. The approach we utilized involved the administration of anti-Abeta antibodies into the hippocampus of the 3xTg-AD mice. Our preliminary findings show that Abeta immunotherapy effectively clears early tau pathology in the brains of the 3xTg-AD mice, although hyperphosphorylated tau aggregates are resistant to clearance. Our results have direct application for the clinical treatment of AD and provide an opportunity to investigate the mechanisms by which Abeta and tau interact. To study the underlying mechanisms by which Abeta and tau lesions are affected by each other the following aims are proposed.
Aim 1 : Determine the impact of clearing Abeta deposits on the onset and progression of tau pathology.
Aim 2 : Determine if phospho-tau specific antibodies can clear hyperphosphorylated tau aggregates, Aim 3: Determine the effect of Abeta and tau clearance on behavior: intraventricular delivery of Abeta and tau antibodies.
Aim 4. Determine the impact of lowering Ap42 levels on the onset and progression of tau pathology. In summary, the implications for AD and other tauopathies is highly significant as it suggests that interventions such as vaccinations will work provided that it is administered early in the disease course, prior to tau hyperphosphorylation. Moreover, these data provide strong evidence for a link between Abeta and tau in an in vivo, physiologically relevant system.
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