Tau Seeding of Neurons Negatively Affects Neuronal Function
Key findings
- Tau propagation is well established to occur in vivo, but no study had addressed how neurons respond to the transfer of tau "seeds"
- This study investigated the effect of the human P301L transgene on individual neurons in an animal model of tauopathy
- A subset of neurons in the cortex developed tau-positive inclusions even though they did not express the transgene, consistent with having received tau seeds
- These recipient neurons showed decreases in synaptic and metabolic markers that have also been shown to occur in humans with Alzheimer's disease
- The results strongly suggest that tau propagation negatively affects neuronal function
Tau protein, which accumulates in multiple neurodegenerative diseases, has been shown in animal models to have the ability to spread throughout the brain. The concept is that aggregates of tau form "seeds" that propagate to other neurons.
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Massachusetts General Hospital's Marta Perez-Rando, PhD, postdoctoral researcher, and Bradley T. Hyman, MD, PhD, director of the Alzheimer's Disease Research Unit at the MassGeneral Institute for Neurodegenerative Disease (MIND), and colleagues have become the first to investigate how these recipient neurons respond to tau uptake. In Acta Neuropathologica Communications, they noted changes in synaptic and metabolic pathways that were similar to changes previously observed in human Alzheimer's disease (AD).
Study Methods
The study made use of rTg4510 transgenic mice. These mice overexpress human tau with the P301L mutation and develop tau aggregates in cortical and hippocampal neurons as they age.
Using RNAScope—high-resolution, multicolor in situ hybridization technology—the team examined the brains of rTg4510 mice that were young (4–6 months of age) or old (12 months of age).
Identification of Recipient Neurons
As expected, RNAScope permitted identification of individual neurons that both overexpressed the human tau transgene and developed tau-positive inclusions. However, a smaller subpopulation of neurons in the cortex developed tau-positive inclusions even though they did not express the transgene—a demonstration of tau seeding. The latter were termed recipient neurons.
Alterations in Recipient Neurons
In both young and old animals, recipient neurons demonstrated decreases in markers of synaptic and metabolic physiology:
- Synaptophysin, the major synaptic vesicle protein
- CAMKIIα, an enzyme critical for long-term potentiation, a mechanism of cortical plasticity
- RNA polymerase II, the enzyme responsible for transcribing most mRNAs
- The general metabolic state of total poly(A) mRNA
In contrast, neurons that developed tau aggregates and also overexpressed the transgene had few changes in the expression of these markers.
Why It Matters
Downregulation of gene expression in neurons bearing tau aggregates has been described in brain tissue from individuals with AD. For example, in a study published in Cell Reports, AD patients showed reduced expression of RNA polymerase II, synaptophysin and CaMKII, compared with non-demented control subjects.
The fact that these differences were recapitulated in a mouse model of tauopathy supports the proposal that aggregation of protopathic tau seeds in recipient neurons negatively affects neuronal well-being.
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