Dementia, one of the symptoms of Alzheimers, stems from the neurofibrillary tangles of which form during the development of the disease. The neurofibrillary tangles consist of tau proteins, abnormal clumps within the neurons, and amyloid beta plaques, which form outside the cell and are often accompanied with neuronal death. Both affect neurons that are involved in memory formation, desecrating these neurons until the tell-tale signs of dementia occur. What is unclear is the timing between the intra- and inter-cellular clumping processes, according to Tong Li, Ph.D assistant professor of pathology at Johns Hopkins.
The extensive research of Alzheimers disease previously suggested that abnormal accumulation of amyloid beta proteins in the brain are somehow triggered by the aggregation of tau and has a direct cause and effect relationship with dementia and neuron degeneration. More recent research, however, suggests that amyloid beta protein accumulation is insufficient in causing the aggregation of neurofibrillary fibers within the neurons that is to say, amyloid beta is not the only factor in the aggregation of tau of which directly leads to dementia.
The Missing Link
Accumulation of amyloid beta protein, on its own, is able to cause brain damage; however, it is not the sole cause of tau aggregation within neurons. Instead, there is evidence that it may set off a chain of chemical signaling events leading to the conversion of tau to a clumping state, thus triggering the development of the symptoms of neuronal loss or cognitive behavioral change. The necessity of tau conversion is the driving force behind dementia, of which manifests in the later stages of Alzheimer's.
Human development of tau amalgamation within neurons and the presence of amyloid beta protein outside of neurons have a 10- to 15-year lag. In order to combat this obstacle while using mice to study dementia due to mice only having a lifespan of 2 to 3 years, Li and others at Johns Hopkins genetically engineered a mouse model to promote the accumulation of normal tau protein via a tau fragment. These mice were then cross-bred with mice genetically engineered to accumulate amyloid beta protein in the same fashion, resulting in a progeny of which developed dementia in a manner that mirrors the incidence in humans.
During brain dissections of these mice models, researchers found that the presence of amyloid beta protein was insufficient to cause the biochemical conversion of tau. The repetition of tau domain (the part of the protein responsible for the conversion of normal tau to an abnormal state) required amyloid beta presence within the brain for the conversion of tau in order for the tau fragments to seed the plaque-dependent pathological conversion of tau.
Philip C. Wong, Ph.D., professor of pathology at the Johns Hopkins University School of Medicine explains the implication of this research and why certain drugs designed to attack the disease after tau conversion are ineffective. If you were to intervene in the time period before the conversion of tau, you might have a good chance of ameliorating the deficits, brain cell loss, and ensuing consequences of the disease, Wong states. A combination therapy targeting prevention of amyloid beta protein as we all the pathological conversion of tau may be the best treatment for Alzheimer's disease. The developed mice model can be utilized to further study future Alzheimers disease therapies.