P3‐059: the Evaluation of Molecular Mechanisms and Translational Biomarkers of Mitochondria‐targeting Therapeutics in Symptomatic Ad Mice
Year: 2019
Type: article
Abstract: We have previously demonstrated that partial reduction of mitochondrial complex I (MCI) activity using small molecules is efficacious in reducing levels of amyloid beta (Aβ) and phosphorylated Tau, augmenting mitochondrial bioenergetics, restoring mitochondrial axonal trafficking, and synaptic proteins in pre-symptomatic APP/PS1 mice. In parallel, these mice demonstrated an improved cognitive and behavioral phenotype compared to their untreated littermates. In our current study, we tested whether treatment with MCI inhibitors could halt the disease progression when treatment was administered to symptomatic APP/PS1 mice (9 months of age). We also evaluated treatment efficacy using multiple parameters informative of healthy aging in chronologically aged non-transgenic (NTG) littermates. Both APP/PS1 and NTG mice displayed improved cognitive and motor abilities following chronic treatment over 13 months compared to untreated counterparts. Treatment improved metabolic outcomes related to aging such as glucose tolerance, prevented body weight loss, and ameliorated systemic inflammation. Treatment improved glucose uptake in the brain measured using FDG-PET imaging. Electrophysiological recording in brain slices indicated that synaptic activity and LTP were restored in the CA1 hippocampal region of treated APP/PS1 mice. Our results gathered from three-dimensional electron microscopy reconstruction of dendrites in CA1 region of hippocampus showed that treatment resulted in higher ratio of active and denser population of mature dendritic spines in APP/PS1 mice, which correlates with restored synaptic activity and improved glucose uptake in the brain. Immunohistochemical analysis showed that treated APP/PS1 mice had reduced brain level of Aβ plaques, reduced degeneration of axons in hippocampus and ameliorated loss of neurons in locus coeruleus. RNA-seq data comparison of differentially expressed genes in the brain of treated vs. untreated APP/PS1 mice depicted a molecular network that clustered around key genes coding for IGF-1 and APP. Protein level analysis in cortico-hippocampal brain region of APP/PS1 mice confirmed that treatment reduced IGF-1 signaling pathway and levels of human APP, but not endogenous mouse APP. Overall, our data suggest that long-term treatment with MCI inhibitors is safe and efficacious in restoring cognitive function and preventing degeneration in symptomatic APP/PS1 mice. Therefore, partial MCI inhibitors represent a promising therapeutic approach to ameliorate AD and promote healthy aging.
Source: Alzheimer s & Dementia
Institutions: Mayo Clinic, University of Minnesota
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980560964