Aging and Progression of Beta-Amyloid Pathology in Alzheimer’s Disease Correlates with Microglial Heme-Oxygenase-1 Overexpression

Abstract

Neuroinflammation and oxidative stress are being recognized as characteristic hallmarks in many neurodegenerative diseases, especially those that portray proteinopathy, such as Alzheimer’s disease (AD). Heme-oxygenase 1 (HO-1) is an inducible enzyme with antioxidant and anti-inflammatory properties, while microglia are the immune cells in the central nervous system. To elucidate the brain expression profile of microglial HO-1 in aging and AD-progression, we have used the 5xFAD (five familial AD mutations) mouse model of AD and their littermates at different ages (four, eight, 12, and 18 months). Total brain expression of HO-1 was increased with aging and such increase was even higher in 5xFAD animals. In co-localization studies, HO-1 expression was mainly found in microglia vs. other brain cells. The percentage of microglial cells expressing HO-1 and the amount of HO-1 expressed within microglia increased progressively with aging. Furthermore, this upregulation was increased by 2–3-fold in the elder 5xFAD mice. In addition, microglia overexpressing HO-1 was predominately found surrounding beta-amyloid plaques. These results were corroborated using postmortem brain samples from AD patients, where microglial HO-1 was found up-regulated in comparison to brain samples from aged matched non-demented patients. This study demonstrates that microglial HO-1 expression increases with aging and especially with AD progression, highlighting HO-1 as a potential biomarker or therapeutic target for AD.

Immune Modulation by Inhibitors of the HO System

“…The second-generation HO inhibitors consist mostly of synthetic imidazole-dioxolane molecules derived from Azalanstat, which has been shown to efficiently inhibit HO activity [ 37 , 38 ]. Currently, both generations of inhibitors are undergoing evaluation for the treatment of diseases, such as cancer [ 39 , 40 ], neurodegenerative diseases [ 41 , 42 , 43 ], and infections [ 44 , 45 , 46 , 47 ]. As research evolves, the modulation of HO activity has also been studied by using various approaches, such as the generation of novel small molecules with an allosteric inhibitory capacity [ 48 ].…”

“…Moreover, high levels of HO-1 have been detected in many pathologies and are associated with a deteriorated inflammatory response, leading to a decrease of the substrate heme and an increase of the anti-inflammatory products, which could impair the development of protective microbial immunity [ 44 , 45 , 46 , 47 ], cancer [ 39 , 40 ], or contribute to neurodegenerative diseases [ 41 , 42 , 43 ]. Along these lines, the administration of HO inhibitors can reduce these anti-inflammatory functions, promoting the development of an appropriate immune response [ 91 , 92 , 93 , 94 ].…”

“…Such a pro-inflammatory and pro-oxidant environment promotes HO-1 expression, particularly in glial cells [ 41 , 115 ]. Consequently, the brain expression pattern of HO-1 has been determined in a murine model of AD [ 41 ].…”

“…Such a pro-inflammatory and pro-oxidant environment promotes HO-1 expression, particularly in glial cells [ 41 , 115 ]. Consequently, the brain expression pattern of HO-1 has been determined in a murine model of AD [ 41 ]. HO-1 was preferentially located within the microglial compartment compared to other brain cells, and most of the microglial cells that overexpressed HO-1 were located near beta-amyloid peptide deposition [ 41 ].…”

“…Consequently, the brain expression pattern of HO-1 has been determined in a murine model of AD [ 41 ]. HO-1 was preferentially located within the microglial compartment compared to other brain cells, and most of the microglial cells that overexpressed HO-1 were located near beta-amyloid peptide deposition [ 41 ]. Furthermore, HO-1 expression in microglial cells increased with aging and was even higher in a mouse model of AD [ 41 ].…”