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On May 20, 2025, Sushil K. Mahata, University of California, published in Nature communications: Chromogranin A deficiency attenuates tauopathy by altering epinephrine- alphaadrenergic receptor signaling in PS19 mice, revealing that chromogranin A deficiency attenuates tauopathy in PS19 mice by altering norepinephrine-alpha-adrenergic receptor signaling.

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Overview

Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions can be reversed in chromogranin A (CgA) knockout mice. CgA is known to be associated with protein aggregation in the brains of patients with neurodegenerative diseases, including AD. The authors investigated the role of CgA in Tau protein lesions in AD and corticobasal ganglia degeneration (CBD). Knockdown of CgA (CgA-KO/PS19) in a mouse model of Tau proteopathy (PS19) reduced the aggregation and spread of pathologic Tau proteins, prolonged lifespan, and improved cognitive function. Transcriptome and metabolite analyses of the mouse cerebral cortex revealed elevated α-1-adrenergic receptor (Adra1) expression and higher epinephrine (EPI) levels in PS19 mice compared to wild-type mice, a phenomenon similar to that observed in AD and CBD patients. In contrast, knockdown of CgA in PS19 mice restored adrenergic levels and Adra1 expression to normal levels in the cortex. In wild-type hippocampal organotypic sections cultured in vitro, treatment with epinephrine or Adra1 agonists promoted hyperphosphorylation of Tau proteins and formation of neurofibrillary tangles, whereas the use of Adra1 antagonists inhibited these processes. These effects were no longer altered in the absence of CgA. These findings suggest that CgA is involved in the development of Tau protein lesions and reveal an important role for the interaction between adrenergic and Adra1 signaling pathways and CgA in Tau protein lesions.

Findings of the Study

• Elevated protein levels of CgA in AD and CBD patient samples and in PS19 transgenic mice

The authors determined CgA protein levels in brain tissue lysates from AD and CBD patients. The results showed that CgA protein levels were significantly higher in frontal cortex and hippocampal lysates of Braak VI AD patients than in Braak 0-II patients and were associated with elevated levels of pathologic Tau protein phosphorylation. In contrast, mRNA levels of CgA did not change significantly between Braak stages. Immunohistochemical analysis of hippocampal tissue from AD patients showed that CgA accumulation was significantly higher in Braak stage VI patients than in Braak stages 0-II. Similarly, elevated CgA levels were found in the frontal cortex of CBD patients. Consistent with human samples, cortical protein blotting and hippocampal immunohistochemistry of PS19 mice showed higher levels of CgA protein than in wild-type mice, but there was no significant difference in mRNA levels of CgA. Co-staining of Braak stage VI hippocampal tissues using antibodies to CgA and specific for misfolded Tau proteins showed a high degree of co-localization of CgA with aggregated Tau tangles.There was weak immunofluorescence for CgA in Braak I or Braak stage 0 hippocampal tissues, and there was no positive staining for MC1. To directly test the effect of CgA on Tau pathology in neurons, the authors cultured primary neurons transduced with AAV2-MAPT (P301S) and treated with precast synthetic Tau fibers (K18/PL). Upon addition of CgA, the MC1 antibody detected a significant increase in misfolded Tau species, confirming the CgA-mediated enhancement of Tau pathology. To investigate how CgA deficiency itself affects Tau phosphorylation and neurofibrillary tangle formation, cultures of hippocampal organotypic slices were isolated from wild-type and CgA-KO pups (postnatal day 7-8) and transduced with TauP301S by AAV, and then seeded and induced with synthetic Tau fibers (K18/PL). Compared with wild-type sections, p-Tau and misfolded Tau species were significantly reduced in CgA-KO sections. These observations suggest that CgA induces a burden of Tau pathology, whereas CgA deficiency attenuates Tau pathology.

• CgA deficiency attenuates Tau proteopathy

To systematically elucidate the role of CgA in Tau-mediated neurodegeneration, the authors crossed PS19 mice with CgA-KO mice to obtain CgA-KO/PS19 mice. At nine months of age, Niebuhr staining showed that PS19 mice developed significant brain atrophy and reduced hippocampal volume. In contrast, CgA-KO/PS19 mice showed only slight brain atrophy. Morphological analysisis of Nissl-stained brain sections showed that the thickness of the dentate gyrus (DG), CA1, and CA3 regions was significantly lower in PS19 mice than in CgA-KO/PS19 and wild-type mice. Protein blotting results of cortical lysates verified the absence of CgA in CgA-KO/PS19 mice. The level of pathological Tau phosphorylation was significantly lower in CgA-KO/PS19 mice compared with PS19 mice. Meanwhile, CgA levels in the cortex of PS19 mice were higher than those of wild-type mice. In addition, postsynaptic density protein 95 (PSD95) levels were significantly decreased in cortical lysates of PS19 mice, indicating the presence of synaptic loss, which was alleviated in CgA-KO/PS19 mice. Protein blotting also showed that p-Tau levels were also significantly reduced in the hippocampal tissue of CgA-KO/PS19 mice. Consistent with the cortical results, PSD95 expression in hippocampal tissue was reduced in PS19 mice and restored in CgA-KO/PS19 mice. p-Tau levels in hippocampal tissue were lower in CgA-KO/PS19 mice than in PS19 mice. In the hippocampus (DG and CA3 regions) of nine-month-old PS19 mice, the number of misfolded Tau proteins was significantly greater than that of CgA-KO/PS19 mice. These results suggest that CgA promotes Tau phosphorylation and neurofibrillary tangle formation. To quantify the difference in the level of Tau seeds with seeding ability in the cortex of PS19 versus CgA-KO/PS19 mice, the authors employed a fluorescence resonance energy transfer assay using HEK293T cells stably expressing CFP/YFP-tagged Tau-RD proteins. The results showed lower FRET signals in crude brain lysates from CgA-KO/PS19 mice, suggesting a diminished Tau seeding capacity. Synthetic K18Tau fibers were injected stereotactically in the dentate gyrus of three-month-old PS19 and CgA-KO/PS19 mice. Six weeks after injection, the CA3 region of the contralateral hippocampus of PS19 mice showed significant fiber-induced pathological spreading of Tau, whereas little such spreading was seen in CgA-KO/PS19 mice, suggesting that CgA facilitates Tau spreading. Further immunohistochemical staining using antibodies to Myc and MC1 showed that the K18 fiber-induced Tau spreading pathology originated from the aggregation of endogenous Tau rather than from the injected K18 fibers per se. The number of synapses in the hippocampus of CgA-KO/PS19 mice was significantly greater than that of PS19 mice, which was consistent with the elevated levels of PSD95 in the cortex and in hippocampal lysates. The synapses in the PS19 mouse The number of synaptic vesicles in preneurons was significantly less than in wild-type and CgA-KO/PS19 mice. In summary, CgA plays a role in promoting neurodegeneration in Tau-induced neurodegenerative lesions.

• CgA Deficiency Improves Spatial Learning and Memory and Extends Lifespan in PS19 Mice

The authors evaluated the behavior of four genotypes of mouse siblings (wild-type, CgA-KO, PS19, and CgA-KO/PS19). In the Morris water maze (MWM) test, during the training phase, PS19 mice needed to swim longer distances and spend more time before finding the platform compared to wild-type and CgA-KO mice and did not show improvement in learning ability throughout the seven days of training, suggesting that spatial learning deficits were present in PS19 mice. In contrast, the learning deficits of CgA-KO/PS19 mice were fully recovered. PS19 mice took longer to enter the target quadrant and made fewer entries, showing impaired memory function, while CgA-KO/PS19 mice performed no significantly differently from wild-type mice. Notably, PS19 mice remained similar to CgA-KO/PS19 mice in terms of body weight and swimming speed, suggesting that the shortened time taken by CgA-KO/PS19 mice to find the platform was not due to faster swimming speed. In the new object recognition (NOR) test, CgA-KO/PS19 mice were more inclined to explore new objects than PS19 mice, indicating improved short-term memory. In addition, in the baton twirling experiment, CgA-KO/PS19 mice showed significantly improved motor function across multiple tests. Taken together, the results of these behavioral tests suggest that knockout of CgA in PS19 mice significantly restores their learning and memory-related behavioral performance. Next, the authors determined the lifespan of PS19 versus CgA-KO/PS19 mice. The results showed that the median lifespan of CgA-KO/PS19 mice was extended to 13.22 months, compared to only 10.12 months for PS19 mice, indicating that CgA deletion significantly extended lifespan by approximately 30%. Notably, 57% of CgA-KO/PS19 mice remained relatively healthy at 12 months of age, with no obvious signs of disease; 23.6% of CgA-KO/PS19 mice survived to 14.5 months, by which time all PS19 mice had died. Taken together, these findings highlight the benefits of knocking out CgA in the PS19 mouse model: not only did it significantly improve cognitive function, but it also effectively mitigated premature death.

• Elevated Epinephrine Levels Exacerbate Tau Proteopathy in OTSC via the α-1 Adrenergic Signaling Pathway in AD, CBD, and PS19 Transgenic Mice

Since both EPI and NE are endogenous agonists of adrenergic receptors, the above results suggest that they may both be involved in Adra1-mediated disease progression. Therefore, the authors examined EPI and NE levels in the prefrontal cortex, hippocampus, and cerebrospinal fluid of AD patients. Significantly elevated levels of EPI were observed in the prefrontal cortex, hippocampus, and cerebrospinal fluid of AD patients with Braak VI compared to Braak stage 0-2 samples. In contrast, there were no significant changes in NE levels in the prefrontal cortex and hippocampus, and instead NE levels in cerebrospinal fluid decreased. Similar to AD samples, prefrontal cortex samples from CBD patients showed higher EPI levels than normal controls, whereas NE levels were not significantly different between CBD patients and controls. EPI concentrations in cerebrospinal fluid were elevated in AD and dementia patients and correlated with disease progression, whereas the difference in NE levels between patients and non-patients was not significant. Both EPI and NE levels were significantly elevated in the cortex of PS19 mice compared with wild-type, CgA-KO, and CgA-KO/PS19 mice. A similar trend was observed in the plasma of PS19 mice, which showed elevated levels of EPI and elevated levels of NE, whereas no significant changes were seen in the levels of NE in CgA-KO and CgA-KO/PS19 mice. Given that both EPI and NE were unable to cross the blood-brain barrier, these results suggest that CgA may play a key role in regulating local catecholamine production in the brain. The authors paid particular attention to the role of EPI since it showed a consistent trend of elevation in PS19 mice as well as in CBD and AD samples. To test the effect of EPI on Tau pathology, EPI treatment experiments were performed in wild-type organotypic section cultures expressing P301S human Tau protein and inoculated with K18 fibers. Protein blotting and immunohistochemical analyses showed that EPI significantly induced Tau phosphorylation and aggregation and that EPI was unable to induce Tau phosphorylation or aggregate formation. These observations highlight the potential role of elevated EPI levels in the development of Tau pathology and suggest that this process is regulated by CgA. To further validate the role of the CgA-EPI-Adra1 signaling axis in the regulation of Tau pathology, the authors co-treated organotypic section cultures with both EPI and PR (an Adra1 antagonist.) Co-treatment of EPI with PR significantly reduced the levels of EPI-induced Tau aggregation and phosphorylation, suggesting that EPI exacerbated Tau pathology.

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Reference

1. Jati, Suborno, et al. "Chromogranin A deficiency attenuates tauopathy by altering epinephrine–alpha-adrenergic receptor signaling in PS19 mice." Nature Communications 16.1 (2025): 1-18. Distributed under Open Access license CC BY 4.0, without modification.