Targeting Mitochondrial Complex I Activity Averts Cognitive Decline in Symptomatic Animal Model of Familial Alzheimer's Disease

Identification: Trushina, Eugenia


Description

Targeting Mitochondrial Complex I Activity Averts Cognitive Decline in Symptomatic Animal Model of Familial Alzheimer's Disease
 
Stojakovic A1, Gateno B1, Tripathi U1, Flannery P1, Trushin S1, Wilkins J1, Trushina E1,2,*.
1Department of Neurology and Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA; 2Department of Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
*Corresponding author
 
Alzheimer's disease (AD) is the leading cause of dementia with an estimated global prevalence of 24 million individuals. Incidences of this disease are expected to double every 20 years emphasizing an urgent need for a development of disease modifying therapeutic strategies. A substantial body of clinical evidence has framed AD in the context of metabolic dysfunction and its pathophysiological importance to disease progression suggesting that modulation of cellular energetics could represent new therapeutic approach. In our previous research, we have demonstrated that modulation of mitochondrial complex I (MCI) activity using small molecules developed is effective in clearing both amyloid beta and phosphorylated Tau, augmenting mitochondrial bioenergetics, promoting resistance to oxidative stress and restoring mitochondrial transport, levels of BDNF and synaptic proteins in presymptomatic APP/PS1 mice. In parallel, these mice demonstrated an improved cognitive and behavioral phenotype over their untreated littermates.  
In our current study, we tested whether treatment with MCI inhibitors could halt the disease progression in symptomatic APP/PS1 mice. We also evaluated treatment efficacy based on multiple parameters informative of healthy aging in chronologically aged non-transgenic (NTG) littermates. Both APP/PS1 and NTG mice displayed improved cognitive and motor performance following chronic treatment over 13 months compared to untreated counterparts. Compound-treated mice displayed reduced levels of senescent cells and inflammation, and APP/PS1 mice had reduced levels of Aβ plaques. We defined the molecular mechanism underpinning this improvement by assessing biochemical pathways involved in the mechanisms of longevity, mitochondrial bioenergetics/signaling, neurotransmitter trafficking, and oxidative stress using multiple techniques and systems biology approaches. Our results suggest that modulation of mitochondrial complex I activity with small molecules represents a promising therapeutic approach to ameliorate AD and promote healthy aging.
 
References: Zhang et al., EBioMedicine, 2015, 2(4):294-305,PMID 26086035
Funding: RF1AG 55549-1; ADDF 20131215.2 (all to ET)

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