Microglial Heme Oxygenase I (HO-1) modulation for the treatment of age-related diseases

Resumen

Aging is the primary risk factor for the development of neurodegenerative diseases (NDDs), such as Alzheimer’s Disease (AD). However, oxidative stress (OS), aberrant protein aggregates and neuroinflammation have been identified as common pathophysiological markers in NDDs. In the specific case of AD, neuroinflammation and OS are key players starting in early stages of the disease. Moreover, intracellular neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau protein, and extracellular senile plaques, consequence of misfolded aberrant amyloid beta (Aβ) protein, are the specific protein aggregates characteristic in AD. Therefore, strategies aiming at modulating neuroinflammation and the formation of aberrant aggregates have gained interest. In this context, the enzyme heme oxygenase I (HO-1) has been proposed as a promising therapeutic target as its activity is linked to anti-inflammatory and anti-oxidant effects. However, the expression pattern of HO-1 and its effects with aging and AD remain controversial. First, to elucidate the brain expression pattern of HO-1 with aging and AD, wild type (WT) and the 5xFAD (five familial AD mutations) mouse model of AD were used at different ages (4, 8, 12 and 18 months). The results from this Doctoral Thesis showed that total brain expression of HO-1 was increased with aging and in AD progression. Interestingly, this HO-1 up-regulation was mainly detected in microglial cells, which are the innate immune cells of the central nervous system (CNS). These findings were corroborated in human postmortem brain samples of AD patients, where HO-1 overexpression was also primarily detected in microglial cells when compared to other CNS cell types. Moreover, microglia overexpressing HO-1 was predominately located surrounding Aβ plaques in the mouse AD model. These findings highlight HO-1 as a potential biomarker or therapeutic target for the treatment of AD. However, whether this up-regulation was a compensatory mechanism to confront the subjacent neuroinflammation or was related to disease progression is still unknown. Therefore, we aimed at studying the effects of microglial HO-1 under inflammatory conditions, both in adult and aged mice. For this purpose, WT and LysMCreHmox1△△ (HMOX1M-KO) mice that lack HO-1 in microglial cells were used. In physiological conditions (adult mice), microglial HO-1 deletion after an inflammatory insult was linked to increased neuroinflammation, OS, cell death and behavioral alterations. However, in aged mice, where microglial HO-1 expression was already significantly up-regulated, the activity of this enzyme after an inflammatory insult was linked to increased levels of iron deposits and thus, augmented OS, neuroinflammation, cell death and cognitive decline. Our results show that both neuroprotective and neurodystrophic actions can be linked to microglial HO-1 activity. Therefore, strategies aiming at modulating HO-1 should be differently considered with regard to the basal expression of this enzyme to achieve beneficial outcomes.