Coupled Neural–Glial Dynamics and the Role of Astrocytes in Alzheimer’s Disease

Abstract

Neurodegenerative diseases such as Alzheimer’s (AD) are associated with the propagation and aggregation of toxic proteins. In the case of AD, it was Alzheimer himself who showed the importance of both amyloid beta (Aβ) plaques and tau protein neurofibrillary tangles (NFTs) in what he called the “disease of forgetfulness”. The amyloid beta forms extracellular aggregates and plaques, whereas tau proteins are intracellular proteins that stabilize axons by cross-linking microtubules that can form largely messy tangles. On the other hand, astrocytes and microglial cells constantly clear these plaques and NFTs from the brain. Astrocytes transport nutrients from the blood to neurons. Activated astrocytes produce monocyte chemoattractant protein-1 (MCP-1), which attracts anti-inflammatory macrophages and clears Aβ. At the same time, the microglia cells are poorly phagocytic for Aβ compared to proinflammatory and anti-inflammatory macrophages. In addition to such distinctive neuropathological features of AD as amyloid beta and tau proteins, neuroinflammation has to be brought into the picture as well. Taking advantage of a coupled mathematical modelling framework, we formulate a network model, accounting for the coupling between neurons and astroglia and integrating all three main neuropathological features with the brain connectome data. We provide details on the coupled dynamics involving cytokines, astrocytes, and microglia. Further, we apply the tumour necrosis factor alpha (TNF-α) inhibitor and anti-Aβ drug and analyze their influence on the brain cells, suggesting conditions under which the drug can prevent cell damage. The important role of astrocytes and TNF-α inhibitors in AD pathophysiology is emphasized, along with potentially promising pathways for developing new AD therapies.