tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β

Area of Science:

• Neuroscience
• Vascular Biology
• Alzheimer's Disease Research

Background:

• Alzheimer's disease (AD) involves amyloid-β (Aβ) peptides, which impair cerebral blood flow (CBF) regulation.
• Tissue plasminogen activator (tPA) is crucial for functional hyperemia but is reduced in AD and Aβ models.
• NMDA receptors (NMDARs) and nitric oxide mediate activity-dependent CBF increases.

Purpose of the Study:

• To investigate the role of tPA in Aβ-induced neurovascular dysfunction.
• To determine if tPA deficiency contributes to the attenuation of functional hyperemia in Aβ models.
• To explore therapeutic potential of modulating the tPA pathway in Aβ-related pathology.

Main Methods:

• Utilized tg2576 transgenic mice expressing the Swedish amyloid precursor protein mutation.
• Measured tPA activity and plasminogen inhibitor-1 (PAI-1) levels.
• Administered exogenous tPA or inhibited PAI-1 pharmacologically/genetically.
• Assessed CBF responses to whisker stimulation and acetylcholine.
• Evaluated cognitive function and cerebral amyloid angiopathy.

Main Results:

• tg2576 mice showed reduced tPA activity and increased PAI-1.
• Restoring tPA activity (via exogenous tPA or PAI-1 inhibition) fully reversed Aβ-induced attenuation of functional hyperemia.
• The beneficial effects were specific to NMDAR-dependent hyperemia, not endothelium-dependent responses.
• PAI-1 inhibition improved cognition and reduced cerebral amyloid angiopathy in tg2576 mice.
• These cognitive and vascular improvements were not linked to reduced amyloid plaques.

Conclusions:

• Aβ accumulation selectively impairs functional hyperemia by reducing tPA activity, mediated by PAI-1 upregulation.
• tPA deficiency suppresses NMDAR-dependent nitric oxide production during neural activity.
• Modulating the PAI-1/tPA pathway offers a potential therapeutic strategy for Aβ-related neurovascular dysfunction and cognitive decline.
• Targeting tPA may be beneficial in diseases characterized by amyloid accumulation, including AD.