OREXIN IN INFLAMMATION AND AGING-RELATED NEURODEGENERATIVE DISEASES

The present doctoral project stemmed from the working hypothesis that the orexin neuropeptides, and in particular OX-A, could be sensitive to neuroinflammatory signaling, including low-grade inflammation implicated in the aging process. The studies focused on testing experimentally, in adult mice of different age groups, the vulnerability of orexin-containing neurons to the exogenous inflammatory challenge represented by exposure to the endotoxin lipopolysaccharide (LPS), and to endogenous mechanisms operant in the murine models of two aging-related neurodegenerative diseases, Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), in which neuroinflammation has been repeatedly implicated. Altogether, the experiments performed in this doctoral project highlight OX-A susceptibility to neuroinflammatory and neurodegenerative conditions. The present data also fill gaps of knowledge indicating increased sensitivity of the orexinergic system in aged animals and animal models of AD and ALS. The deposition of β-amyloid in the hypothalamus of aged transgenic models of AD is another novel finding of this study. The vulnerability of orexinergic neurons could be important for sleep-wake disturbances and for alterations in energy homeostasis in neuroinflammatory and neurodegenerative conditions, and could be implicated in cognitive decline in aging-related neurodegenerative diseases. Keywords: Orexin, hypocretin, astrocytes, microglia, neuroinflammation, neurodegeneration, aging, Alzheimer’s disease, amyotrophic lateral sclerosis