Therapeutic targeting and implications of AMPK mediated autophagy by naringenin against amyloid and#946; evoked neurotoxicity

Abstract

Alzheimer s disease (AD) is a complex neurodegenerative disease with dual clinicopathology. AD is clinically characterized by amyloid-and#946; plaques, tau tangles that leads to behavioural impairments and eventually to neuronal degeneration. Accumulation of the amyloid-and#946; peptide is among the primary events in the pathophysiology of Alzheimer s disease (AD). The converging lines of studies suggest that both early-onset AD (EOAD) and late-onset AD (LOAD) have disproportionate accumulation of pernicious forms of amyloid-and#946;. Amyloid-and#946; is eliminated from the brain through different clearance mechanisms such as blood-brain barrier (BBB) transport, interstitial fluid (ISF) bulk flow, degradation, and cerebrospinal fluid (CSF) in synergy. The dysregulation in any of these mechanisms leads to disease lesions. Considerably, the deposition of amyloid-and#946; reflects the inefficiency of proteolytic systems for its proper clearance which, in part, is attributed to the decreased capacity of cellular degradation, mainly the autophagic lysosomal system. The vital correlation between autophagy and and#946;-amyloid clearance has received enormous appreciation from the past two decades. A substantial number of evidence build on targeting the skewness in the production and degradation of amyloid-and#946; as an appealing therapy in the disease. Neuronal autophagy has emerged for an essential role in the degradation of toxic aggregate-prone proteins also in various other neurodegenerative diseases. We profiled a library of common natural compounds and evaluated those that can enhance autophagy in different neural systems. Here we noted from molecular simulations that naringenin exhibited a strong affinity with AMP-activated protein kinase (AMPK) and upregulated AMPK-mediated autophagy signaling in Neuro2a cells and primary mouse neurons. Protein expression assay by western blotting and confocal imaging for autophagic makers LC3-II and p62 revealed autophagy flux was increased in response to naringenin. Naringenin can induce autophagy promoting proteins.