940C Poster - 15. Models of human disease
Saturday April 09, 1:30 PM - 3:30 PM

Authors:
Celya D. Dahmani ¹; Julia O'Connell ²; Timothy O'Toole ¹; Kenneth J. Colodner ²; Geoffrey R. Tanner ^1,3

Affiliations:
1) University of Connecticut, Storrs, CT; 2) Mount Holyoke College, South Hadley, MA; 3) Institute for the Brain and Cognitive Sciences, Storrs, CT

Keywords:
a. neural degeneration; c. nutrition

Tauopathies are a class of neurodegenerative diseases characterized by abnormal intracellular aggregations of the microtubule-stabilizing protein tau. Symptomology of tauopathies features impaired cognition—including difficulties with learning and memory—caused by progressive neuronal and synaptic degeneration. Tau pathology is often characterized by an accumulation of hyperphosphorylated tau protein resulting in the formation of neurotoxic tau aggregates, also known as neurofibrillary (NFT) and gliofibrillary (GFT) tangles. These aggregates may hinder neural glycolytic metabolism and result in degradation of the myelin sheath and other glial components. Ketone bodies (KBs), metabolites of the putatively-neuroprotective high-fat and low-carbohydrate ketogenic diet (KD), bypass cytoplasmic glycolysis and enter directly into mitochondrial metabolism. The KD and KBs serve to elevate cellular ATP/ADP ratio and thus may rescue neural energetics. We have obtained evidence strongly suggesting that KBs may exhibit neuroprotective effects in a Drosophila melanogaster model of traumatic brain injury (TBI); repeated TBI may lead to the progressive neurodegenerative condition termed Chronic Traumatic Encephalopathy (CTE), which is characterized in part by intracellular aggregation of tau protein in neural cells. We employed a Drosophila model of tauopathy that allows for spatial restriction of exogenous tau protein overexpression to glial cells and for temporal restriction of tau overexpression to adulthood, so as to avoid developmental effects of neural tau protein overexpression. We directly applied a racemic mixture of the KD metabolite beta-hydroxybutyrate (β-HB)—the major circulating ketone body (KB)—to a standard high-carbohydrate Drosophila diet to determine whether dietary KB supplementation can ameliorate tauopathy-associated learning deficits. We found that β-HB markedly improves tauopathy-induced learning deficits in mixed-sex groups of adult Drosophila and reduces levels of phosphorylated tau in the brains of male flies subjected to induced glial tauopathy.