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.
Highlights
Alzheimer’s disease (AD), the most common form of dementia, and other neurodegenerative diseases (NDDs) share common pathological mechanisms such as oxidative stress (OS), low-grade inflammation, mitochondrial dysfunction, metal imbalance and protein aggregation
Other studies show that in non-demented subjects, Heme-oxygenase 1 (HO-1) immunoreactivity was low, though detectable, in various cell types, such as astrocytes, cerebrovascular endothelial cells, or choroid plexus epithelial cells, in different brain regions [23,24]. These results indicate that, during physiological aging, HO-1 could be up-regulated in specific cells and areas of the brain that may be vulnerable to oxidative stress as an adaptive defense mechanism
Induction of HO-1 was significantly increased in the thalamus and amygdala at 18 months of age in the 5xFAD mice in comparison to WT, both in male and female mice, with the exception of the thalamus of female 5xFAD mice, where significant increase of HO-1 was observed at the earlier age of 12 months (Figure 1K)
Summary
Alzheimer’s disease (AD), the most common form of dementia, and other neurodegenerative diseases (NDDs) share common pathological mechanisms such as oxidative stress (OS), low-grade inflammation, mitochondrial dysfunction, metal imbalance and protein aggregation. Many of these alterations occur during physiological aging, which is considered the major risk factor to develop AD. APP undergoes proteolysis by α-secretase, leading to a soluble APP fragment involved in the homeostasis of synaptic transmission. In AD, APP undergoes abnormal proteolysis, first by β-secretase and γ-secretase, leading to the formation of Aβ peptides Aβ40 and Aβ42
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