# Chromogranin A Deficiency Attenuates Tauopathy by Altering Epinephrine–Alpha-Adrenergic Receptor Signaling

## TL;DR

This study shows that Chromogranin A deficiency reduces tau-related brain damage by altering epinephrine and adrenergic receptor signaling in mice.

## Contribution

The study reveals a novel mechanism linking Chromogranin A to tauopathy through epinephrine-Adra1 signaling.

## Key findings

- CgA-KO/hTau mice showed reduced tau aggregation and improved cognitive function.
- CgA deficiency reversed elevated epinephrine and Adra1 expression in tauopathy models.
- EPI and Adra1 agonists increased tau hyperphosphorylation, while antagonists reduced it.

## Abstract

Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A knockout (CgA-KO) mice. This study investigates the role of CgA in Alzheimer’s disease (AD) and corticobasal degeneration (CBD). CgA ablation in tauopathy mice (hTau) (CgA-KO/hTau) exhibited reduced tau aggregation, spreading, extended lifespan, and improved cognitive function. Transcriptomic and metabolite analysis of mouse cortices revealed altered alpha1-adrenergic receptors (Adra1) and high epinephrine (EPI) levels in hTau mice compared to WT mice, mirroring observations in AD and CBD patients. CgA-KO/hTau mice exhibited a reversal of EPI levels in the cortex and the expression of Adra1, nearly returning them to WT levels. Treatment of hippocampal slices with EPI or Adra1 agonist intensified, while an Adra1 antagonist inhibited tau hyperphosphorylation and aggregation. These findings highlight the interplay between the EPI-Adra signaling system and CgA in tauopathy.