Summary: New research reveals how tau pathology spreads and damages synapses in progressive supranuclear palsy (PSP). Using human postmortem tissue and live human brain slice models, scientists demonstrated that tau accumulates in both presynaptic and postsynaptic terminals and likely propagates neuron to neuron through synaptic contacts.
Synapses containing tau were more prone to loss, and reactive astrocytes were observed engulfing tau-laden synapses. These findings identify synaptic tau as a central driver of PSP and a promising therapeutic target.
Key Facts
- Synaptic tau spread: Pathological tau builds up on both sides of the synapse, supporting direct neuron-to-neuron transmission via synaptic connections.
- Astrocytic engulfment: Reactive astrocytes remove synapses that contain tau, contributing to synapse loss and circuit disruption.
- Therapeutic implications: Blocking tau’s entry into synapses or its toxic interactions there could slow PSP progression and preserve neuronal circuits.
Source: Neuroscience News
Progressive supranuclear palsy (PSP) is a relentless neurodegenerative disorder that impairs balance, movement, and cognition. Central to PSP is tau, a neuronal protein that, when abnormally modified and aggregated, spreads through the brain and contributes to neuronal dysfunction and loss.
Although links between tau pathology and synapse loss have been recognized, the mechanisms by which tau damages synapses and traverses between neurons were unclear. The new study addresses this gap by focusing on the synapse—the primary site of neuron-to-neuron communication.
Combining analyses of postmortem human brain tissue with experimental work in live human cortical slice cultures, researchers provide strong evidence that tau directly invades synapses, undermines synaptic integrity, and triggers glial responses that further reduce synapse number.
The Curious Case of Tau
Under normal conditions, tau stabilizes microtubules inside neurons. In tauopathies such as PSP and Alzheimer’s disease, tau becomes abnormal—hyperphosphorylated and prone to aggregate—leading to neuronal dysfunction and death. In PSP, tau pathology advances in a characteristic pattern across brain regions, and regions with heavier tau burden show more pronounced synapse loss and clinical impairment.
A central question has been whether tau simply accumulates in already damaged areas or actively spreads through neuronal networks and causes the damage. To investigate this, the research team examined synaptic structures directly.
Tau Invades Synaptic Pairs
Using high-resolution imaging on postmortem PSP brains, the study found that oligomeric (toxic) forms of tau frequently localize to both sides of individual synapses—present in the presynaptic terminal and the opposing postsynaptic density. Quantitatively, postsynaptic elements were far more likely to contain tau when their paired presynapse also harbored tau, a pattern consistent with trans-synaptic propagation.
Super-resolution microscopy revealed tau closely associates with synaptic proteins such as synaptogyrin-3, corroborating prior animal studies that linked tau–synaptic protein interactions to synaptic dysfunction. Importantly, synapses containing tau were significantly more likely to be lost, underscoring tau’s direct synaptotoxic effects.
Astrocytes Join the Attack
The researchers also examined the role of glial cells, particularly astrocytes, which normally support neurons and maintain synaptic homeostasis. In PSP tissue, astrocytes showed reactive changes and increased engulfment of synapses compared with controls. Many of the synapses consumed by astrocytes contained tau, suggesting that astrocytes may recognize tau-laden synapses as damaged and remove them—an otherwise protective process that may inadvertently accelerate synapse loss and network decline.
A Living Human Brain Slice Model
To test whether tau can actively enter postsynapses and elicit astrocytic responses in living tissue, the team used live human cortical slices obtained during neurosurgical procedures. Exposure to soluble tau extracted from PSP brains led to rapid accumulation of tau in postsynaptic terminals and to increased astrocyte reactivity and synaptic engulfment, mirroring the postmortem findings.
This model demonstrates that human synapses can actively take up pathological tau and that synaptic tau accumulation and astrocyte-driven synapse removal are not simply downstream effects of cell death but represent dynamic processes in viable tissue.
Clusterin: A New Accomplice?
Proteomic analysis identified elevated clusterin in PSP synapses, and imaging showed clusterin colocalized with tau in postsynaptic regions at distances consistent with molecular interaction. Clusterin, previously implicated in Alzheimer’s disease, may facilitate tau’s entry into synapses or enhance its toxicity there, making it a potential new target for therapeutic investigation.
Why This Matters
By demonstrating that oligomeric tau propagates across synapses, damages synaptic structures, and prompts astrocyte-mediated clearance of those synapses, the study pinpoints synaptic tau as a central mediator of PSP progression. Strategies that block tau’s synaptic entry, neutralize toxic tau oligomers at synapses, or modulate astrocytic phagocytosis could protect neuronal circuits and slow disease progression. Indeed, monoclonal antibodies that target synaptic tau oligomers are under investigation in clinical trials.
The findings also suggest PSP may involve plastic, targetable processes rather than exclusively irreversible damage, offering renewed hope for developing effective therapies.
Looking Ahead
Open questions remain: why are some synapses more susceptible to tau accumulation, can astrocytic overactivity be tuned to reduce harmful synapse loss, and to what extent do similar synaptic tau mechanisms operate in related tauopathies such as Alzheimer’s disease and frontotemporal dementia? Future research will explore these avenues, with the goal of translating mechanistic insights into interventions that protect synapses—the critical nodes of brain communication.
By focusing on synaptic tau and the glial responses that follow, this research reframes our understanding of PSP and highlights new paths for therapy development.
About this PSP and neurology research news
Author: Neuroscience News Communications
Source: Neuroscience News
Contact: Neuroscience News Communications
Image: The image is credited to Neuroscience News
Original Research: Open access. “Evidence for trans-synaptic propagation of oligomeric tau in human progressive supranuclear palsy” by Robert I. McGeachan et al., Nature Neuroscience
Abstract
Evidence for trans-synaptic propagation of oligomeric tau in human progressive supranuclear palsy
In progressive supranuclear palsy (PSP), tau pathology spreads through the brain in a stereotyped pattern, coinciding with regional synapse loss. We tested whether pathological tau contributes to synapse loss and spreads by moving from presynapses to postsynapses. Using postmortem PSP brain samples and a living human brain slice culture model, we observed pathological tau in synaptic pairs and found that oligomeric tau can enter live human postsynapses. Proteomics revealed increased clusterin in PSP synapses, and super-resolution imaging showed clusterin colocalized with tau in synapses at proximities consistent with binding, which may mediate tau spread. Tau accumulation at synapses correlated with synapse loss, and synaptic engulfment by astrocytes was observed, suggesting astrocytic contribution to synapse elimination. Together, these data indicate that targeting synaptic tau is a promising approach to treating PSP.