Hedgehog Signaling in the Brain Contributes to Alzheimer’s Disease in a Drosophila Model

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Abstract: Hedgehog (Hh) signaling plays critical roles in pattern formation, embryonic development, and cell growth control; however, its function(s) in adulthood remain largely unknown although the mylfunction of Hh signaling causes several types of cancer. Hh signaling has also been shown to be involved in neurodegenerative disease and shown to regulate the proliferation of neuroal stem cells. It is unknown whether Hh signaling is involved in Alzheimer’s disease. Transduction of the Hh signal requires the G protein-coupled receptor (GPCR) family protein Smoothened (Smo) in both insects and mammals. Recent studies have demonstrated that cholesterol activates Smo through direct interaction and possibly covalent attachment. Whether and how cholesterol biosynthesis pathway regulates Smo are unclear. We recently discovered that Hh signaling activity maintains the viability of dopaminergic neurons in Drosophila adult brain. Inactivation of Hh signaling significantly decreased the lifespan of adult flies. In addition, we identified a non-canonical cholesterol biosynthesis pathway that critically regulates Smo. We have established a Alzhermer’s disease model by expressing human amyloid beta (Aβ) in adult flies. We hypothesize that the non-canonical cholesterol biosynthesis pathway plays a role in compromising the defects caused by Aβ expression. We will determine whether cholesterol biosynthesis protects dopaminergic neurons in the adult brain and modulates Drosophila lifespan (Aim 1). We will determine whether cholesterol biosynthesis provide a protective effect in Aβ-induced neurodegeneration of the Alzheimer’s disease model (Aim 2). Proposed studies use a combination of genetic and biochemical approaches to build on prior contributions and to transition to newly emergent avenues of inquiry. The knowledge gained from this study will provide novel insights into mechanisms of Hh signaling in the protection of neurodegeneration and Alzheimer’s disease.