Astrocytic Propagation of Tau in the Context of Alzheimer's Disease

Abstract

More than 6 million Americans are currently living with Alzheimer's disease (AD), and the incidence is growing rapidly with our aging population. Numerous therapeutics have failed to make it to the clinic, potentially due to a focus on presumptive pathogenic proteins instead of cell-type-specific signaling mechanisms. The tau propagation hypothesis that inter-neuronal tau transfer drives AD pathology has recently garnered attention, as accumulation of pathological tau in the brain has high clinical significance in correlating with progression of cognitive AD symptoms. However, studies on tau pathology in AD are classically neuron-centric and have greatly overlooked cell-type specific effects of tau internalization, degradation, and propagation. While the contribution of microglia to tau processing and propagation is beginning to be recognized and understood, astrocytes, glial cells in the brain important for maintaining neuronal metabolic, synaptic, trophic, and immune function which can produce, internalize, degrade, and propagate tau are understudied in their ability to affect AD progression through tau pathology. Here, we showcase evidence for whether tau uptake by astrocytes may be beneficial or detrimental to neuronal health and how astrocytes and their immunometabolic functions may be key targets for future successful AD therapies.

Tau Seeding Mouse Models with Patient Brain-Derived Aggregates

“…Astrocytic transcription factor EB also plays a role in clearing the extracellular space of pathological tau species in Tg mice following seeding with PFFs [ 144 ], identifying also a potential key role for astrocytes in tau propagation. These findings illustrate that it may be worth further exploring and elucidating the involvement of glial cells in tauopathies (reviewed in [ 145 ]).…”

Andrographolide Attenuates Gut-Brain-Axis Associated Pathology in Gulf War Illness by Modulating Bacteriome-Virome Associated Inflammation and Microglia-Neuron Proinflammatory Crosstalk

“…The endothelial cells of the BBB have pronounced crosstalk with the above cell types and are often responsible for maintaining homeostasis [ 73 ]. Microglia and astrocytes play an important role in immune regulation, but many inflammatory phenotypes such as that seen in Alzheimer’s disease (AD) or Parkinsonism result from proinflammatory actions of these cell types [ 74 , 75 ]. For example, microglial activation may result in the release of proinflammatory cytokines such as IL-1β, MCP-1 that in turn can activate the surrounding astrocytes for roles that may perturb neurogenesis and synaptic plasticity [ 76 , 77 ].…”

Disrupting Neurons and Glial Cells Oneness in the Brain—The Possible Causal Role of Herpes Simplex Virus Type 1 (HSV-1) in Alzheimer’s Disease

“…Pathological tau present in glial cells also exerts propagation across the brain, e.g., oligodendroglial tau aggregates spread along white matter tracts, ultimately leading to the loss of oligodendrocytes [ 210 ]. In addition to neurons, astrocytes also produce, internalize, and degrade tau, and participate in tau propagation in the brain, also possibly influencing AD progression [ 177 ]. Interestingly, glial tau aggregates can supplement neuronal tau aggregates in the same degenerating brain regions [ 195 ].…”