The epinephrine-alpha-1 adrenergic receptor (Adra1) signaling axis represents a newly characterized pathogenic pathway in corticobasal syndrome (CBS) and related 4R tauopathies. Research published in 2025 demonstrates that elevated epinephrine (EPI) levels and increased Adra1 expression drive tau hyperphosphorylation and neurofibrillary tangle formation, while chromogranin A (CgA) — a key regulator of catecholamine storage and release — plays a protective role against tau pathology. [1]
This pathway provides a mechanistic link between the noradrenergic system, stress response, and tau pathogenesis in CBS, and suggests therapeutic targets including Adra1 antagonists and chromogranin A augmentation strategies.
Chromogranin A (CgA, encoded by the CHGA gene) is a member of the granin family of acidic secretory proteins. It is synthesized and stored in dense-core secretory granules of catecholamine-producing cells, including:
CgA serves multiple functions:
The 2025 study by Jati et al. in Nature Communications established a complete mechanistic pathway linking CgA deficiency to tauopathy progression: [1:1]
CgA Deficiency: In PS19 tauopathy mouse models, genetic deletion of Chga leads to significantly reduced CgA protein levels. This mirrors observations in human corticobasal degeneration (CBD) and Alzheimer's disease brains, where CgA expression is decreased.
Disinhibited EPI Release: Without adequate CgA, the negative feedback control on epinephrine release is lost. Chromaffin cells and LC nerve terminals release excess EPI into the synaptic cleft and extracellular space.
Elevated Cortical EPI: The study measured significantly elevated cortical EPI levels in Chga-deficient mice, consistent with the high EPI levels observed in postmortem CBS and CBD brain tissue.
Adra1 Upregulation: EPI acts primarily through Gq-coupled alpha-1 adrenergic receptors. CgA normally suppresses Adra1 transcription; when CgA is low, Adra1 mRNA and protein levels increase substantially in cortical and hippocampal neurons.
Tau Hyperphosphorylation: Adra1 activation triggers a cascade involving PKC, Ca2+ influx through L-type channels, and activation of tau kinases (GSK3-beta, CDK5). This results in hyperphosphorylation of tau at multiple epitopes (AT8, AT180, PHF-1).
NFT Formation and Neuronal Loss: Hyperphosphorylated tau aggregates into paired helical filaments and neurofibrillary tangles, leading to synaptic loss and neuronal death.
The Jati et al. study demonstrates several findings directly relevant to CBS: [1:2]
| Finding | Evidence |
|---|---|
| Elevated EPI in CBS/CBD brains | Postmortem tissue from CBD patients shows elevated cortical EPI vs. age-matched controls |
| Adra1 overexpression in tauopathies | Human CBD brain tissue shows increased ADRA1A/ADRA1B mRNA and protein |
| CgA reduction in CBS | Immunohistochemistry shows reduced CgA in LC and adrenal tissue of CBS patients |
| Therapeutic benefit of Adra1 blockade | Terazosin (selective Adra1 antagonist) reduced tau pathology in PS19 mice |
| Critical window for intervention | Adra1 blockade was most effective when started before heavy NFT burden |
Three Adra1 subtypes exist:
Therapeutic targeting preferentially should focus on ADRA1A and ADRA1B in the context of CBS.
Existing FDA-approved Adra1 antagonists may have repurposing potential:
These drugs block Adra1-mediated tau hyperphosphorylation and reduce NFT formation in mouse models. Human epidemiological studies show reduced neurodegeneration risk in patients taking alpha-1 blockers for urological conditions. [2]
Gene therapy or protein replacement approaches to increase CgA levels represent a more targeted but experimental strategy.
Since the LC is the primary source of brain EPI, interventions that protect LC neurons from degeneration (e.g., noradrenergic neuroprotection, reducing oxidative stress) could indirectly reduce pathogenic EPI signaling.
CBS frequently presents with mixed proteinopathies. The relationship between Adra1 signaling and TDP-43 pathology: [3]
Jati S, Munoz-Mayorga D, Shahabi S, et al. Chromogranin A deficiency attenuates tauopathy by altering epinephrine-alpha-adrenergic receptor signaling in PS19 mice. Nature Communications. 2025. ↩︎ ↩︎ ↩︎
Various. Atomoxetine Drug Properties for Repurposing as a Candidate Alzheimer Disease Therapeutic Agent. Various. 2025. ↩︎
Nasir AR, Delpirou Nouh C. TDP-43-proteinopathy at the crossroads of tauopathy: on co-pathology and current and prospective biomarkers. Frontiers in Cellular Neuroscience. 2025. ↩︎