The Role of Astrocyte-Derived Toxic Lipids Mediating Degeneration in Alzheimer’s Disease

2021

Astrocytes, star-shaped support cells of the central nervous system (CNS), have essential roles in brain development and normal functioning. They also have well-described responses to disease termed “astrocyte reactivity,” characterized by profound changes in the genes these cells express and how well they perform important normal functions. Gene expression analysis of reactive astrocytes highlights multiple different types, with novel markers for each. Recent genetic association studies have implicated many disease-associated genes that almost exclusively are associated with support cells, like astrocytes, in patients with a range of neurodegenerative diseases, including Alzheimer’s disease (AD). Beyond pathogenic proteins like amyloid and tau, astrocytes are implicated in the onset and progression of AD. In addition, immune cells, which provoke inflammation in the CNS, also are major contributors. Inflammation itself represents a balance between beneficial (e.g., removing dead cells) and detrimental (e.g., increased cell death) effects. Immune cells, and the inflammation they induce, inform reactive astrocytes at the site of disease—leading to devastating expansion of the pathology.

During AD, one reactive astrocyte substrate switches from a support role to a pathological one: slowing neuron communication, decreasing connections between neurons and becoming less efficient at removing waste products—detrimental to all of these processes that are important for a healthy and normally functioning brain. In extreme cases, these astrocytes secrete a toxin that kills neurons. We have localized these toxic reactive astrocytes to regions of dead and dying neurons in both animal models of AD and in human patients. Importantly, we find this neurotoxic function does not depend on the underlying genetics of individual patients. This makes targeting neurotoxic reactive astrocytes an exciting novel avenue for the development of new therapies.

Our methods to maintain positive components of inflammation and target only the production and release of a specific astrocyte neurotoxin provide unrivaled control over this complex system. We will investigate the role astrocyte-derived neurotoxins have in the initiation and progression of AD. Results from these studies will give us a better understanding of basic astrocyte biology, and will provide new targets for development of future therapies.


Funding to Date

$174,754

Focus

Studies of Innate Immune Pathology, Translational

Researchers

Shane Liddelow, Ph.D.