Increased expression of the γ‐secretase components presenilin‐1 and nicastrin in activated astrocytes and microglia following traumatic brain injury

Abstract

Gamma-secretase is an aspartyl protease composed of four proteins: presenilin (PS), nicastrin (Nct), APH1, and PEN2. These proteins assemble into a membrane complex that cleaves a variety of substrates within the transmembrane domain. The gamma-secretase cleavage products play an important role in various biological processes such as embryonic development and Alzheimer's disease (AD). The major role of gamma-secretase in brain pathology has been linked to AD and to the production of the amyloid beta-peptide. However, little is known about the possible role of gamma-secretase following acute brain insult. Here we examined by immunostaining the expression patterns of two gamma-secretase components, PS1 and Nct, in three paradigms of brain insult in mice: closed head injury, intracerebroventricular injection of LPS, and brain stabbing. Our results show that in naïve and sham-injured brains expression of PS1 and Nct is restricted mainly to neurons. However, following insult, the expression of both proteins is also observed in nonneuronal cells, consisting of activated astrocytes and microglia. Furthermore, the proteins are coexpressed within the same astrocytes and microglia, implying that these cells exhibit an enhanced gamma-secretase activity following brain damage. In view of the important role played by astrocytes and microglia in brain disorders, our findings suggest that gamma-secretase may participate in brain damage and repair processes by regulating astrocyte and microglia activation and/or function.

Epigallocatechin-3-gallate prevents systemic inflammation-induced memory deficiency and amyloidogenesis via its anti-neuroinflammatory properties

“…These data indicated that LPS activates astrocytes, and activated astrocytes released these cytokines. Activation of astrocytes is also known to lead to elevated β-secretase activity [52][53][54] as well as γ-secretase activity [55], consequently increasing Aβ generation. In this present study, we also found that LPS induced an increase of colocated activated astrocytes and amyloid plaque.…”

Emerging roles of the γ-secretase-notch axis in inflammation

“…Epidemiological studies have indicated that head trauma and ischemia are important factors contributing to AD dementia. PS1 and nicastrin expression have been found to increase in activated microglia and astrocytes following traumatic brain damage, including closed-head injuries, stabbing-related head trauma, and inflammatory insults, indicating enhanced γ-secretase activity in those cells (Nadler et al, 2008). Indeed, treatment with a γ-secretase inhibitor in an experimental stroke model in mice improves outcome by reducing pro-inflammatory leukocyte infiltration, microglial activation, NF-κB activation and hypoxia inducible factor (HIF)-1α signaling (Arumugam et al, 2006Cheng et al, 2014;Park et al, 2011;Park et al, 2013).…”

Oxidative Stress and β-Amyloid Protein in Alzheimer’s Disease

“…Normal astrocytes can degrade Ab, suggesting that abnormal astrocytes damaged by oxidative stress can increase Ab generation and accumulation. Since the major role of b/c-secretase in brain pathology has been linked to AD and to the production of the Ab, b/c-secretase may participate in the cleavage of APP and Ab generation via activation of astrocyte and microglia by oxidative stress (Nadler et al 2008;Rossner et al 2005).…”