Alzheimer’s disease (AD) is a progressive neurodegenerative disease that represents a major cause of death in many countries. AD is characterized by profound memory loss, disruptions in thinking and reasoning, and changes in personality and behavior followed by malfunctions in various bodily systems. Although AD was first identified over 100 years ago, and tremendous efforts have been made to cure the disease, the precise mechanisms underlying the onset of AD remain unclear. The recent development of next-generation sequencing tools and bioinformatics has enabled us to investigate the role of genetics in the pathogenesis of AD. In this review, we discuss novel discoveries in this area, including the results of genome-wide association studies (GWAS) that have implicated a number of novel genes as risk factors, as well as the identification of epigenetic regulators strongly associated with the onset and progression of AD. We also review how genetic risk factors may interact with age-associated, progressive decreases in cognitive function in patients with AD.
SUMMARYThe lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Chemogenetic inhibition of GABRA5LHA suppresses energy expenditure and increases weight gain, whereas gene-silencing of Gabra5 in LHA decreases weight gain. In DIO mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Gene-silencing of astrocytic MAOB in LHA reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a MAOB inhibitor, KDS2010. We propose that firing of GABRA5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.
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