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tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β.

TitletPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β.
Publication TypeJournal Article
Year of Publication2020
AuthorsPark L, Zhou J, Koizumi K, Wang G, Anfray A, Ahn SJi, Seo J, Zhou P, Zhao L, Paul S, Anrather J, Iadecola C
JournalJ Neurosci
Volume40
Issue42
Pagination8160-8173
Date Published2020 Oct 14
ISSN1529-2401
Abstract

The amyloid-β (Aβ) peptide, a key pathogenic factor in Alzheimer's disease, attenuates the increase in cerebral blood flow (CBF) evoked by neural activity (functional hyperemia), a vital homeostatic response in which NMDA receptors (NMDARs) play a role through nitric oxide, and the CBF increase produced by endothelial factors. Tissue plasminogen activator (tPA), which is reduced in Alzheimer's disease and in mouse models of Aβ accumulation, is required for the full expression of the NMDAR-dependent component of functional hyperemia. Therefore, we investigated whether tPA is involved in the neurovascular dysfunction of Aβ. tPA activity was reduced, and the tPA inhibitor plasminogen inhibitor-1 (PAI-1) was increased in male mice expressing the Swedish mutation of the amyloid precursor protein (tg2576). Counteracting the tPA reduction with exogenous tPA or with pharmacological inhibition or genetic deletion of PAI-1 completely reversed the attenuation of the CBF increase evoked by whisker stimulation but did not ameliorate the response to the endothelium-dependent vasodilator acetylcholine. The tPA deficit attenuated functional hyperemia by suppressing NMDAR-dependent nitric oxide production during neural activity. Pharmacological inhibition of PAI-1 increased tPA activity, prevented neurovascular uncoupling, and ameliorated cognition in 11- to 12-month-old tg2576 mice, effects associated with a reduction of cerebral amyloid angiopathy but not amyloid plaques. The data unveil a selective role of the tPA in the suppression of functional hyperemia induced by Aβ and in the mechanisms of cerebral amyloid angiopathy, and support the possibility that modulation of the PAI-1-tPA pathway may be beneficial in diseases associated with amyloid accumulation. Amyloid-β (Aβ) peptides have profound neurovascular effects that may contribute to cognitive impairment in Alzheimer's disease. We found that Aβ attenuates the increases in blood flow evoked by neural activation through a reduction in tissue plasminogen activator (tPA) caused by upregulation of its endogenous inhibitor plasminogen inhibitor-1 (PAI-1). tPA deficiency prevents NMDA receptors from triggering nitric oxide production, thereby attenuating the flow increase evoked by neural activity. PAI-1 inhibition restores tPA activity, rescues neurovascular coupling, reduces amyloid deposition around blood vessels, and improves cognition in a mouse model of Aβ accumulation. The findings demonstrate a previously unappreciated role of tPA in Aβ-related neurovascular dysfunction and in vascular amyloid deposition. Restoration of tPA activity could be of therapeutic value in diseases associated with amyloid accumulation.

DOI10.1523/JNEUROSCI.1140-20.2020
Alternate JournalJ Neurosci
PubMed ID32928888
PubMed Central IDPMC7574658
Grant ListR01 NS037853 / NS / NINDS NIH HHS / United States
R01 NS097805 / NS / NINDS NIH HHS / United States
R01 NS100447 / NS / NINDS NIH HHS / United States