Alzheimer’s Disease Creates a Positive Feedback Loop of Excitatory Signaling in Brain Networks
Post by Rebecca Hill
The takeaway
Beta-amyloid and tau are proteins that aggregate in two distinct networks in the brain in Alzheimer’s disease. When there are higher beta-amyloid and tau protein levels, the neuronal networks switch from inhibitory to excitatory signaling, leading to a positive feedback loop of excitation and further protein build-up.
What's the science?
In individuals affected by Alzheimer’s disease, the disruption of normal brain functioning is linked to a build-up of b-amyloid and tau proteins. Early in the progression of Alzheimer’s disease, beta-amyloid proteins build up in the association cortex (the default mode network, also known as the DMN), which is usually active when a person is daydreaming or at rest. Tau proteins on the other hand tend to appear in the entorhinal cortex (in the medial temporal lobe, also known as the MTL), which mainly facilitates memory processing. It’s still unclear why this protein aggregation occurs in two different networks in the brain. This week in Neuron, Giorgio and colleagues investigated this difference in protein aggregation by examining how these two different networks in the brain interact using brain imaging.
How did they do it?
The authors recruited 66 individuals (45 older adults without symptoms of Alzheimer’s and 21 young adults) for this study. A subset of these individuals had evidence of beta-amyloid and tau protein build-up reminiscent of early-stage Alzheimer’s disease. The authors asked participants whether an image presented to them was new or repeated while undergoing brain imaging to measure activity in the association and entorhinal cortices. Typically, neuronal activity is suppressed when viewing an image that has already been seen before. However, previous research has found that Alzheimer’s patients cannot suppress neuronal activity well during these tasks. The authors used functional MRI (fMRI) to measure brain activity and PET scans to measure the amount of beta-amyloid and tau proteins present in the two brain regions.
What did they find?
For participants with low levels of b-amyloid and tau proteins, there was inhibitory signaling between the DMN and the MTL for repeated images, indicating normal brain functioning with an ability to suppress neuronal activity. However, for participants whose protein levels were higher in the two brain regions, there was excitatory signaling instead. This indicates that Alzheimer’s disease alters normal brain functioning by causing neurons to fire excitatory signals from each brain region to the other. As more beta-amyloid builds up in these networks, there is more excitatory signaling to other networks, further increasing the amount of tau building up in the other networks. This creates a positive feedback loop of excitation between these networks, leading to further build-up of beta-amyloid and tau proteins.
What's the impact?
This study is the first to show how Alzheimer’s disease develops in the association and entorhinal cortices by creating a positive feedback loop of excitatory neuronal signaling. This causes abnormal brain functioning in individuals with Alzheimer’s disease by preventing their ability to suppress brain activity in response to new stimuli. Understanding how Alzheimer’s disease develops may help with our ability to diagnose and treat individuals affected by it.