Abstract & Commentary
Synopsis: These findings provide compelling evidence in favor of the amyloid cascade hypothesis, which suggests that Aß leads to the development of hyperphosphorylated tau aggregates within neurons.
Source: Oddo, et al. Aß Immunotherapy Leads to Clearance of Early, But Not Late, Hyperphosphorylated Tau Aggregates Via the Proteasome. Neuron. 2004:43,321-332.
Amyloid beta (Aß) plaques and neurofibrillary tangles are the histologic hallmarks of the neuropathology of Alzheimer’s disease (AD). The relationship of Aß deposition to the development of neurofibrillary tangles however, has been unclear. Recently, a triple transgenic mouse model of AD, which has both Aß deposits, as well as tau pathology, has been developed. These mice have mutations in the amyloid precursor protein, a mutated gene for presenilin 1, and a mutant form of the tau gene. The rodents develop plaques and tangles in the cortex, amygdala, and hippocampus, just as people with AD do. The plaques precede the tangles, consistent with the idea that Aß build up is the initiating factor.
In the present study, Oddo and colleagues have generated direct evidence that Aß contributes to the generation of neurofibrillary tangles, which are composed of hyperphosphorylated tau aggregates. Oddo et al injected their triple transgenic mice with anti-Aß antibodies administered into the hippocampus. Oddo et al showed that there was a reduction in the extracellular Aß deposits, as well as intracellular Aß, which occurs rapidly, and that this also reduces early tau pathology. The Aß deposits were cleared within 3 days, and the tau lesions required a slightly longer timepoint and were not reduced until 5 days postinjection. The Aß, therefore, cleared first followed by the clearance of tau localized in the somatodendritic compartment of the neurons. At 30 days after the injections, the Aß deposits had reemerged. In a second group of animals, the antibodies erased plaques in 6-month and 12-month old animals. They also cleared pretangle tau aggregates in the 6-month old animals, but had no effect in the 1-year old mice, in which the tau had become hyperphosphorylated. Oddo et al also used an alternative approach in which they administered an inhibitor of g-secretase, which leads to similar results. This once again will reduce the generation of Aß. These findings, therefore, provide compelling evidence in favor of the amyloid cascade hypothesis, which suggests that Aß leads to the development of hyperphosphorylated tau aggregates within neurons. The clearance of these aggregates was dependent on the proteasome, since it was blocked by proteasome inhibitors.
The present results show that clearance of Aß early in the disease process prevents the development of hyperphosphorylated tau aggregates, which contributes to the generation of neurofibrillary tangles. This is the most direct evidence to date linking Aß to the generation of neurofibrillary tangles. It is consistent with recent neuropathologic studies of patients treated with Aß immunization. This clinical trial had been halted due to an excess of brain inflammation. Several of these patients who came to autopsy, however, showed a clearance of Aß, yet persistent neurofibrillary tangles. The results indicate that Aß targeted therapies may be useful for clearing both Aß plaques and the neurofibrillary tangles of AD, provided that the intervention occurs early in the course of the illness. — M. Flint Beal, MD
Dr. Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY, is Editor of Neurology Alert.