Systemic Piezo1 activation improves cerebrovascular function in Alzheimer's disease

Area of Science:

• Neuroscience
• Vascular Biology
• Pharmacology

Background:

• Alzheimer's disease (AD) is characterized by reduced cerebral blood flow (CBF) and impaired functional hyperemia (FH).
• These cerebrovascular deficits are early features contributing to AD progression.

Purpose of the Study:

• To investigate the effect of systemic Piezo1 activation on cerebrovascular deficits in a mouse model of AD.
• To determine if targeting the mechanosensitive ion channel Piezo1 can ameliorate AD-related vascular dysfunction.

Main Methods:

• Utilized two-photon in vivo imaging and laser-speckle imaging in the 5xFAD mouse model of AD.
• Assessed CBF, capillary stalling, and FH in response to whisker stimulation.
• Administered the Piezo1 agonist Yoda1 systemically.

Main Results:

• 5xFAD mice exhibited increased capillary stalling and reduced CBF and FH compared to wild-type controls.
• Yoda1 administration significantly reduced capillary stalls by approximately 65%.
• Yoda1 treatment increased CBF and improved FH in 5xFAD mice, restoring responses to control levels.

Conclusions:

• Piezo1 activation enhances microvascular flow and neurovascular coupling in the context of AD.
• Piezo1 represents a promising therapeutic target for addressing early cerebrovascular dysfunction in Alzheimer's disease.