Title : Abnormal mitochondrial dynamics and defective synapses: Protective role of reduced dynamin-related protein 1 in alzheimer’s disease
Synaptic pathology and mitochondrial oxidative damage are early events in AD progression. Loss of synapses and synaptic damage are the best correlates of cognitive deficits found in AD patients. Recent research on Aβ, tau mitochondria and synapses in AD revealed that Aβ and tau accumulates in synapses and synaptic mitochondria, leading to abnormal mitochondrial dynamics and synaptic degeneration in AD neurons. Further, recent studies using live-cell imaging and primary neurons from amyloid precursor protein transgenic mice revealed reduced mitochondrial mass, defective axonal transport of mitochondria and synaptic degeneration, indicating that Aβ is responsible for mitochondrial and synaptic deficiencies. We recently found that abnormal physical interaction between mitochondrial fission protein, Drp1 and Aβ and Drp1 and phosphorylated tau (p-Tau), leading to excessive mitochondrial fragmentation, reduced mitochondrial fusion (Manczak et al 2011 Hum Mol Genet and Manczak and Reddy 2012 Hum Mol Genet). Based on these observations, we hypothesized that a partial reduction of Drp1 inhibits and Drp1and Aβ and Drp1-pTau interactions and protects neurons from pTau-induced mitochondrial and synaptic toxicities, and maintains neuronal function in AD progression. To test our hypothesis, we created double mutant (Drp1+/-xTau and Drp1+/-xAPP. Using molecular, biochemical, Golgi-cox staining and transmission electron microscopy studies, we investigated mRNA, protein levels of mitochondrial dynamics, biogenesis, autophagy and synaptic genes, dendritic spines, mitochondrial number and morphology and Morris Water Maze based cognitive behavior in 12-month-old Drp1+/-x Aβ and Drp1+/-xTau mice. We found significantly increased dendritic spines, significantly reduced fragmented and structurally damaged mitochondria and reduced mRNA and protein levels of fission genes and increased levels of fusion, biogenesis, autophagy and synaptic genes in the brains of 12-month-old Drp1+/-x Aβ and Drp1+/-xTau mice relative to age-matched APP and Tau mice. Importantly, we also found ameliorated cognitive deficits in 12-month-old Drp1+/-xAPP and Drp1+/-xTau mice relative to age-matched APP and Tau mice. These observations strongly suggest that reduced Drp1 is beneficial to AD neurons and may have a therapeutic value to AD patients.