ApoE4 expression disrupts tau uptake, trafficking, and clearance in astrocytes
Abstract
Tauopathies are a collection of neurodegenerative diseases characterized by the accumulation of pathogenic aggregates of the microtubule‐associated protein tau. Despite the prevalence and diversity of tau astrogliopathy in tauopathies, the interactions between astrocytes and tau in the brain, and the influence of neurodegenerative genetic risk factors like the apolipoprotein E4 (apoE4) isoform, are largely unknown. Here, we leveraged primary and immortalized astrocytes expressing humanized apoE isoforms to characterize the mechanisms by which astrocytes interact with and eliminate extracellular tau, and the influence of apoE genotype on these processes. Our work indicates that astrocytes rapidly internalize, process, and release tau via an exosomal secretory mechanism under physiological conditions. However, we found that apoE4 disrupted these processes in comparison to apoE3, resulting in an astrocytic phenotype prone to intracellular tau accumulation. Furthermore, exposure to repetitive mild traumatic brain injuries exacerbated the apoE4‐induced impairments in tau processing and elimination by astrocytes in apoE4 targeted‐replacement mice. The diminished ability of apoE4 astrocytes to eliminate extracellular tau can lead to an accumulation of pathogenic tau, which induces mitochondrial dysfunction, as demonstrated by our studies. In total, our findings suggest that the apoE4 isoform lowers the threshold of astrocytic resilience to pathogenic tau, rendering them susceptible to bioenergetic deficits in the early stages of neurodegenerative diseases such as traumatic brain injury, potentially contributing to neurological decline.
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APOE ε4 impairs tau uptake and trafficking, potentially exacerbating tau pathology.
“The efficiency of tau processing is influenced by APOE isoforms, with APOE ε4 impairing tau uptake and trafficking, potentially exacerbating tau pathology.”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [16]
Cites
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LRP1 is a master regulator of tau uptake and spread
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BackgroundDisease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria
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“As such, bypassing the autophagosome system may avoid pathogenic protein spread and toxicity, in a similar manner to what has been observed with α -synuclein (Fussi et al., 2018).”
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Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes
Tian, X., Rivera, E. K., Hwang, I., Nikitina, A. A., Smith, J. A., Cho, Y. J., Sala‐Jarque, J., DuBose, A., Andriola, C., Gollan‐Myers, T., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70589 · Cited by 7 · see citing works
- Authors
- Eisenbaum, M., Pearson, A., Ortiz, C., Mullan, M., Crawford, F., Ojo, J., & Bachmeier, C.
- Affiliations
- The Roskamp Institute Sarasota Florida USA
- ORCID
- Eisenbaum, Maxwell
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2023-09-05
- Volume
- 72
- Issue
- 1
- Pages
- 184-205
- ISSN
- 0894-1491
- 1098-1136
- Cited by
- 27
- References
- 21
- Language
- en
- Funders
- U.S. Department of Defense (W81XWH1910344‐PRARP‐CSRA)
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