Study of modulator function of klotho protein in neuroinflammatory signaling in mice

Abstract

The increase in life expectancy of the world population creates the need for understanding the aging process. This process induces alterations in organic functions at different levels of biological complexity which are directly related to the appearance of diseases. In the 90s, the discovery of a deletion in the gene that encodes the Klotho protein, in rodents, was shown to drastically decrease the levels of this protein, leading to a 90% reduction of the lifespan. This is accompanied by an early onset of age-related syndromes such as arteriosclerosis, osteoporosis, skin atrophy, pulmonary emphysema, reduction of synapse number in the hippocampus, axonal transport deficit, hippocampal and motor neuron degeneration accompanied by cognitive decline. In agreement with these findings, overexpression of Klotho was shown to increase rodents' lifespan by 30% and trigger cognitive and memory improvement. The Klotho protein is mainly expressed in the distal renal tubules, choroid plexus, and in regions of the central nervous system (CNS) such as cerebellar Purkinje cells and hippocampus. In renal tissue, Klotho has an anti-inflammatory role through the inhibition of the nuclear factor kB (NF-kB) activation and subsequent production of inflammatory cytokines in response to the tumor necrosis factor (TNF-±) stimulation. Taking into account the role of Klotho in renal inflammation, this project aims to investigate the neuroprotective role of Klotho against acute neuroinflammation induced by lipopolysaccharide inflammatory agent (LPS) in mice brain. We will assess behavioral adaptive responses related to cognitive and memory deficits induced by LPS over treatment with Klotho. In addition, we will analyze the ability of Klotho to modulate synaptic activity and plasticity through electrophysiology. These approaches will be complemented with evaluation of biochemical responses related to neuroinflammation and plasticity in the hippocampus, prefrontal cortex and cerebellum, structures which undergo changes in NFkB levels. Neuroinflammation is a key event in the establishment, development and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. Therefore, the results obtained in this project will contribute to the discovery of new molecular targets which can be used in the development of therapies aimed at alleviating or even halt the progression of those diseases.