CROSSTALK OF MITOCHONDRIA TO SYNAPTIC DYSFUNCTION IN ALZHEIMER DISEASE

Abstract

Diabetes is considered to be a risk factor in Alzheimer’s disease (AD) pathogenesis and has adverse effects on the brain, especially the hippocampus, which is particularly susceptible to synaptic injury and cognitive dysfunction. The underlying mechanisms and strategies to rescue such injury and dysfunction are not well understood. Combination of in vitro neuronal culture and in vivo diabetes and Alzheimer's disease mouse models to study mitochondrial function, dynamics, axonal mitochondrial transport, and synaptic function including pre- and post-synaptic morphology and activity. To detemine the effect of AD-related mitochondrial defects, we also examined AD- or MCI-derived mitochondria in neuronal cybrid cells incoporated with mitochondria from platelets of patients with Alzheimer's disease. Our most recent studies point to a novel role of mitochondrial dynamics and transport in diabetes- and AD-induced synaptic impairment. Inhibition of excessive mitochondrial fission induced by hyperglycemia, oxidative stress, and amyloid beta in vitro and in vivo diabetes and AD models significantly improves mitochondrial and synaptic function. Additionally, blockade of mitochondrial membrane transition pore restores synaptic mitochondrial function and synaptic transmission. Furthermore, inhibition of either excessive mitochondrial fission or cyclophilin D-induced mitochondrial transition pore improves AD-mitochondrial defects. Blockade of activation of MAPkinase (p38 phosphorylation) reverses these detrimental effects, suggesting the contribution of oxidative stress-induced signaling to mitochondrial dysfunction relevant to AD pathology. Our studies indicate that synaptic mitochondria play a key role in synaptic plasticity and transmission in diabetes- and Alzheimer's disease-insulted abnormalities. Thus, exploration the mechanisms behind diabetes-induced synaptic deficit may provide a novel treatment of mitochondrial and synaptic injury in patients with diabetes beyond management of high glucose. Targeting mitochondria-mediated alterations in dynamics, mitochondrial transition pore, and bioenergy may be a potential for the tratement of diabetes as well as Alzheimer's disease. This study is supported by NIH.