Kidney Week

Abstract: FR-PO567

Pkd1 Mutation Causes Memory Impairment Driving by Cellular Senescence in ADPKD

Session Information

• Genetic Diseases: Cystic - Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Firdaus, Zeba, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Zeba Firdaus,

• Mao, Xinyue, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xinyue Mao,

• Li, Lu, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Lu Li,

• Li, Xiaoyan, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xiaoyan Li,

• Zhou, Xia, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xia Zhou,

• Harris, Peter C., Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Peter C. Harris,

• Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xiaogang Li,

Background

Cellular senescence is a hallmark of aging. It plays a crucial role in a wide variety of age-related diseases and neuronal disorders. Accumulation of senescent cells in the brain leads to structural and functional changes and result in memory impairment. It is not clear whether Pkd1 mutation results in memory impairment in ADPKD patients. We hypothesize that Pkd1 mutation impairs memory in mice through cellular senescence signaling.

Methods

To test our hypothesis, we performed behavioral experiments (Y-maze and novel object recognition test) to evaluate the memory deficit in wild type and Pkd1^RC/RC mice. To understand the underlying molecular mechanisms, we isolated cerebral cortex and hippocampus from wild type and Pkd1^RC/RC brain and then performed Western blot, qRT-PCR, and immunostaining analysis.

Results

We observed an impairment of hippocampal and cortical dependent memory with novel object recognition and Y-maze test in Pkd1^RC/RC mice. To understand the underlying molecular mechanisms, we found that the expression of PSD-95, a synaptic marker, and neural growth factor BDNF was decreased in Pkd1 mutant brains compared to wild type controls, and thus resulting in synaptic dysfunction and memory impairment. The downregulation of PSD-95 and BDNF was regulated by the RE-1 silencing transcription factor (REST), which was downregulated in Pkd1 mutant mouse brain. Mutation of Pkd1 also resulted in the accumulation of macrophages in mouse brain as examined with F4/80 staining. We further found that cellular senescence was increased in Pkd1 mutant mouse brain as seen by the increase of p16. The mRNA levels of senescence associated secretory proteins (SASP), including CCL2, IL1-β, IL6, and TNF-α, were upregulated, which contribute to neuroinflammation as seen by the increase of the accumulation of activated microglial cells in Pkd1 mutant mouse brain. The increased SASP level was regulated by the activation of JAK/STAT signaling in Pkd1 mutant mouse brain.

Conclusion

This is the first study to show that Pkd1 mutation causes memory loss and cognitive impairment in mouse brain via the accumulation of senescent cells to increase SASP production, which causes activation of microglial cells and downregulation of REST, resulting in synaptic dysfunction.

Funding

• NIDDK Support