Downregulating PTBP1 Fails to Convert Astrocytes into Hippocampal Neurons and to Alleviate Symptoms in Alzheimer's Mouse Models

• DOI: 10.1523/jneurosci.1060-22.2022
• Publication Date: 2022-08-09T17:50:22Z
• Authors: Tiantian Guo; Xinjia Pan; Guangtong Jiang; Denghong Zhang; Jinghui Qi; Lin Shao; Zhanxiang Wang; Huaxi Xu; Yingjun Zhao
• Keywords: 0303 health sciences; 03 medical and health sciences

Conversion of astroglia into functional neurons has been considered a promising therapeutic strategy for neurodegenerative diseases. Recent studies reported that downregulation the RNA binding protein, polypyrimidine tract-binding protein 1 (PTBP1), converts astrocytes <i>in situ</i> in multiple mouse brain regions, consequently improving pathologic phenotypes associated with Parkinson9s disease, RGC loss, and aging. Here, we demonstrate PTBP1 using an astrocyte-specific AAV-mediated shRNA system fails to convert hippocampal both male female wild-type (WT) β-amyloid (5×FAD) tau (PS19) Alzheimer9s disease (AD) models reverse synaptic/cognitive deficits AD-associated pathology mice. Similarly, cannot striatum substantia nigra WT Together, our study suggests cell fate conversion therapy through manipulating one single gene, such as PTBP1, warrants more rigorous scrutiny. <b>SIGNIFICANCE STATEMENT</b> Our results do not support some recent extraordinary revolutionary claims resident can be directly efficiently converted neurons. is critical field neural regeneration degeneration. In addition, financially important because it may prevent other researchers/organizations from wasting vast amount time resources on relevant investigations.