Complement C3a receptor antagonist alleviates tau pathology and ameliorates cognitive deficits in P301S mice

by Selleckchem | Nov 18 2023

Human tauopathies, including Alzheimer's disease (AD), are a major class of neurodegenerative diseases characterized by intracellular deposition of pathological hyperphosphorylated forms of Tau protein. Complement system is composed of many proteins, which form a complex regulatory network to modulate the immune activity in the brain. Emerging studies have demonstrated a critical role of complement C3a receptor (C3aR) in the development of tauopathy and AD. The underlying mechanisms by which C3aR activation mediates tau hyperphosphorylation in tauopathies, however, remains largely unknown. Here, we observed that the expression of C3aR is upregulated in the brains of P301S mice - a mouse model of tauopathy and AD. Pharmacologic blockade of C3aR ameliorates synaptic integrity and reduced tau hyperphosphorylation in P301S mice. Besides, the administration of C3aR antagonist (C3aRA: SB 290157) improved spatial memory as tested in the Morris water maze. Moreover, C3a receptor antagonist inhibited tau hyperphosphorylation by regulating p35/CDK5 signaling. In summary, results suggest that the C3aR plays an essential role in the accumulation of hyperphosphorylated Tau and behavioral deficits in P301S mice. C3aR could be a feasible therapeutic target for the treatment of tauopathy disorders, including AD.

Comments:

The passage you provided highlights a significant finding in the field of neurodegenerative diseases, particularly in the context of tauopathies and Alzheimer's disease (AD). Here's a breakdown of the key points mentioned in the passage:

### 1. **Background:**
- **Tauopathies:** Neurodegenerative diseases, including Alzheimer's disease, are characterized by the accumulation of hyperphosphorylated forms of the Tau protein within brain cells.
- **Complement System:** A complex network of proteins that regulate immune activity in the brain.

### 2. **Research Findings:**
   - **C3aR Upregulation:** The expression of C3aR is increased in the brains of P301S mice, a mouse model of tauopathy and AD.
   - **C3aR Blockade:** Pharmacological blockade of C3aR improves synaptic integrity, reduces tau hyperphosphorylation, and enhances spatial memory in P301S mice.
   - **C3aRA Administration:** Administering a C3aR antagonist (C3aRA: SB 290157) improves spatial memory, suggesting a potential cognitive benefit.
   - **Mechanism:** C3aR antagonist inhibits tau hyperphosphorylation by regulating the p35/CDK5 signaling pathway.

### 3. **Implications:**
- **Therapeutic Target:** The study suggests that C3aR could be a viable therapeutic target for tauopathy disorders, including Alzheimer's disease.
- **Behavioral Impact:** Blocking C3aR not only reduces pathological tau accumulation but also improves behavioral deficits in the mouse model.

### 4. **Conclusion:**
- The results imply that C3aR activation is instrumental in the development of tauopathy and AD.
- By understanding and targeting the mechanisms involving C3aR, researchers might develop treatments to mitigate the progression of tauopathies, providing potential hope for Alzheimer's disease patients.

This research sheds light on a potential avenue for therapeutic intervention in Alzheimer's disease and related tauopathies. Further studies and clinical trials will likely be conducted to explore the efficacy and safety of targeting C3aR as a treatment strategy for these debilitating neurological disorders.