Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice

Authors

Peng Yu, Henry Ford Health
Poornima Venkat, Henry Ford HealthFollow
Michael Chopp, Henry Ford HealthFollow
Alex ZacharekFollow
Yi Shen, Henry Ford HealthFollow
Liang Liang, Henry Ford HealthFollow
Julie Landschoot-Ward, Henry Ford HealthFollow
Zhongwu Liu, Henry Ford HealthFollow
Rongcai Jiang
Jieli Chen, Henry Ford HealthFollow

Recommended Citation

Yu P, Venkat P, Chopp M, Zacharek A, Shen Y, Liang L, Landschoot-Ward J, Liu Z, Jiang R, and Chen J. Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice. Aging Dis 2019; 10(4):770-783.

Document Type

Article

Publication Date

8-1-2019

Publication Title

Aging Dis

Abstract

Tissue plasminogen activator (tPA) is a serine protease primarily involved in mediating thrombus breakdown and regulating catabolism of amyloid-beta (Abeta). The aim of this study is to investigate age-dependent decline of endogenous tPA and the effects of tPA decline on glymphatic function and cognitive outcome in mice. Male, young (3m), adult (6m) and middle-aged (12m) C57/BL6 (wild type) and tPA knockout (tPA(-/-)) mice were subject to a battery of cognitive tests and white matter (WM) integrity, neuroinflammation, and glymphatic function were evaluated. Adult WT mice exhibit significantly decreased brain tPA level compared to young WT mice and middle-aged WT mice have significantly lower brain tPA levels than young and adult WT mice. Middle-aged WT mice exhibit significant neuroinflammation, reduced WM integrity and increased thrombin deposition compared to young and adult mice, and increased blood brain barrier (BBB) permeability and reduced cognitive ability compared to young WT mice. In comparison to adult WT mice, adult tPA(-/-) mice exhibit significant BBB leakage, decreased dendritic spine density, increased thrombin deposition, neuroinflammation, and impaired functioning of the glymphatic system. Compared to age-matched WT mice, adult and middle-aged tPA(-/-) mice exhibit significantly increased D-Dimer expression and decreased perivascular Aquaporin-4 expression. Compared to age-matched WT mice, young, adult and middle-aged tPA(-/-) mice exhibit significant cognitive impairment, axonal damage, and increased deposition of amyloid precursor protein (APP), Abeta, and fibrin. Endogenous tPA may play an important role in contributing to aging induced cognitive decline, axonal/WM damage, BBB disruption and glymphatic dysfunction in the brain.

PubMed ID

31440383

Volume

10

Issue

4

First Page

770

Last Page

783