Amyloid Beta and Tau Synergize to Impair Neural Circuits in Alzheimer's Disease
Key findings
- Researchers used two distinct mouse models of Alzheimer's disease to better replicate the disease in humans
- Brain activity was diminished in still living neurons in mice that had neurofibrillary tangles and increased in mice that had amyloid plaques
- Neuronal silencing dominated over hyperactivity when Aß and tau were present together
- Reducing the tau protein (that makes tangles) reversed the damaging effect on brain activity
- The tau molecule, rather than tangles per se, seems to be the most important cause of the effect on brain function. This might change the target for therapeutic approaches
Studies suggest that in patients with Alzheimer's disease (AD), it is the interaction between amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles that causes pathology. The tangles form first in limbic areas, then spread outward to the neocortex, which is already affected by plaques. This propagation of tau into the cortex has been linked to the transition from the preclinical stage of AD to the stage where people develop symptoms.
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What hasn't been known is how the Aβ–tau interaction affects intact neuronal circuits. To investigate, Bradley T. Hyman, MD, PhD, director, Massachusetts Alzheimer's Disease Research Center, and colleagues combined the two Alzheimer's models so both Aβ and tau pathology present in the cortex, like patients with AD. To their surprise, they found that the two proteins have dramatically opposing effects on neuronal circuits, with tau dominating over Aβ.
Most investigational disease-modifying therapies for AD target Aβ or tau, but none targets both. In Nature Neuroscience, the researchers explain why their findings have important implications for drug development.
Aβ Promotes Neuronal Hyperactivity, While Tau Suppresses Activity
The researchers first used in vivo two-photon calcium imaging to examine neurons in APP/PS1 transgenic mice, which develop only Aβ plaques without tau pathology. They detected neuronal hyperactivity in the transgenic mice compared with wild-type controls.
The opposite experiment was to analyze neurons in age-matched rTg4510 transgenic mice, which overexpress human tau and develop neurofibrillary tangles but not Aβ pathology. In stark contrast to the earlier results, all rTg4510 mice showed a highly significant reduction of cortical activity: a 3.6- to 5.8-fold increase in the proportion of "silent" neurons, with virtually no neuronal hyperactivity.
Moreover, impairment of neurons occurred independently of tau aggregation, the researchers found. Specifically, they observed that elevated tau was associated with significantly reduced neural activity in rTg21221 transgenic mice, which overexpress human tau but do not form neurofibrillary tangles.
Combination of Aβ and Tau Leads to Suppressed Neuronal Activity
To determine the net effect of Aβ and tau together, the researchers imaged six- to 12-month-old bi-transgenic mice, including:
- Crosses of APP/PSI and rTg4510 mice
- Crosses of APP/PSI and rTg21221 mice
Unexpectedly, not only was neuronal hyperactivity completely abolished in both APP/PS1–rTg4510 mice and APP/PS1–rTg21221 mice, but the animals showed a strong reduction in cortical activity levels.
The researchers then studied three- to four-month-old rTg4510 mice and APP/PSI–rTg4510 mice, which were too young to exhibit overt neuropathology and neurodegeneration. Even so, imaging revealed a significant reduction in neuronal activity in the APP/PSI–rTg4510 mice and not in the rTg4510 mice.
The scientists conclude that when Aβ and tau are present together in the cortex, tau blocks Aβ-dependent hyperactivity, resulting in profound silencing of neuronal circuits. This second set of observations also reinforces the earlier finding that neurofibrillary tangles are not critical for suppression of neuronal activity.
In the Presence of Aβ, Tau Reduction Is Less Effective in Rescuing Neuronal Impairment
rTg4510 and rTg21221 mice are bred so that their expression of tau can be suppressed by using doxycyclin. The researchers found that, in the same individual mice, impaired neuronal circuit function could be completely reversed by suppressing tau expression, despite the continued presence of neurofibrillary tangles in rTg4510 mice.
By comparison, none of the APP/PS1–rTg4510 and APP/PS1–rTg21221 mice showed any change in proportions of silent neurons after doxycycline treatment.
The respective results were the same in three- to four-month-old mice. Neuronal impairment in young rTg4510 mice significantly improved after doxycycline treatment, whereas in young APP/PS1–rTg4510 mice, it remained unchanged.
Research Implications
Dr. Hyman and his colleagues note that their results fit with certain clinical observations:
- Patients with AD exhibit a progressive decrease of whole-brain activity and slowing of the electroencephalogram
- Tau, rather than Aβ, determines cognitive status
- Drugs that suppress Aβ have been relatively unsuccessful in recent clinical trials
The research team finds it particularly intriguing that suppression of tau rescued neuronal impairments in tau mice, whereas it was significantly less effective when Aβ was also present. It may be that synaptic and cellular changes are more severe in the presence of Aβ–tau interactions than with Aβ or tau alone.
They note that aggregated tau in neurofibrillary tangles is the target in several ongoing clinical trials, and they suggest that analyses and data presentations in these trials need to be reconsidered.
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