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.

Keywords: Alzheimer's disease; astrocyte; inflammation; tau internalization; tau propagation.

Figure 1

The impact of astrocytes on tau propagation in AD. Neurons contain tau on their microtubules (Yamada, 2017). Tau can become hyperphosphorylated and dissociate from the microtubules due to a myriad of factors (Mandelkow and Mandelkow, ; Fichou et al., 2019). Stimulated or dying neurons can release tau into the extracellular space (Pooler et al., ; Wu et al., ; Pernègre et al., 2019) 14-16, where astrocytes are known to internalize tau (de Calignon et al., ; Asai et al., ; Martini-Stoica et al., ; Perea et al., 2018, 2019). Astrocytic internalization rates may be affected by a number of factors, including cholesterol levels; APOE status; and tau concentration, aggregation state, and isoform. Following internalization, astrocytes may (1) degrade the internalized tau, (2) release the tau back out of the cell, potentially propagating the pathological tau to healthy neurons, and (3) accumulate tau, potentially triggering inflammatory cytokine release, which can harm neuronal health.