Project 460600

Alzheimer disease (AD) is a progressive neurodegenerative disease characterized by neurofibrillary amyloid plaques and hyperphosphorylated tau tangles that result in cognitive impairment, sleep disturbances, and other behavioral abnormalities. It is the most common form of dementia, a public health burden, with an annual cost to Canada of over $10 billion/year. Sleep disturbance occurs with increased amyloid beta levels suggesting circadian disturbance is part of the causal pathway leading to AD. Astrocytes are the regulators of sleep behavior in flies, mice, and humans via a mechanism termed the astrocyte-neuron-lactate-shuttle (ANLS). Lactate release by ANLS from astrocytes is tied to glutamatergic synaptic activity, and lactate provides the metabolic needs of neighboring neurons as an energy substrate. Studies in mice have shown that astrocytic expression of the proteins low-density lipoprotein receptor (LRP) and ApoE regulate amyloid-beta clarence and astrocyte dysfunction increases amyloid-beta aggregation. In the absence of aggregation in mice, daily oscillations in amyloid-beta are tied to the sleep-wake cycle and wake-related lactate levels. Endogenous neural activity regulates regional changes in amyloid-beta, resulting in local amyloid-beta aggregation, which is associated with the concentration of lactate, supporting the idea that the ANLS is involved in AD. The research will show the astrocyte-neuron-lactate-shuttle (ANLS) linked to sleep-wake states which leads to amyloid-beta oligomerization. I will use an optical-sensor method and two-photon calcium in C57BL/6 mice. By using the iGluSnFR biosensor(pAAV.hSynapsin.SF-iGluSnFR.A184S), I can view and quantify glutamate expression and the L-lactate biosensor (gfaABC1D-eLACCO2.1) expression in head-restrained mice running on a treadmill. Understanding the neuronal mechanisms responsible for this feedback relationship between sleep, amyloid-beta, and AD pathology will provide insight into treatments of AD.