Role of Histone Deacetylase in AD Mitochondrial Dysfunction
Our data will provide direct evidence of the relationship between mitochondrial trafficking, function and memory. Data will validate the axonal trafficking of mitochondria as a therapeutic target; reveal the mechanism of HDAC1 toxicity in the pathogenesis of AD and provide the mechanistic explanation for therapeutic role of HDAC inhibitors.
Histone deacetylase 1 (HDAC1) is a protein that controls gene activity. Problems with HDAC1 can both disrupt the activities of other genes, and can promote cell death by disrupting movement of the mitochondria, the cell's “energy powerhouses.” Dr. Eugenia Trushina, Dr. Joseph Poduslo, and colleagues will look for what specifically causes the problem with mitochondrial movement. In particular, they'll look at the effect of beta‐amyloid proteins on mitochondrial motility in cultured cells and in brain slices from mice with Alzheimer's. Once they pinpoint the mechanism of dysfunction, the next step would be to create and test drugs that restore the mitochondrial transport and, hopefully, prevent progression of the disease.
Dr. Trushina’s team has recently demonstrated that mitochondrial dysfunction occurs early in disease progression in three commonly used mouse models of familial Alzheimer’s disease (FAD), irrelevant of the origin of the type of FAD gene mutation (Trushina et al., PLoS ONE, 2012). Changes in mitochondrial dynamics and function in nerve cells of these mice were detected prior to the onset of neurological and memory problems, and before the formation of amyloid deposits in the brain. The increased susceptibility of neurons to excitotoxic cell death was found to be due to inhibition of mitochondrial trafficking in the neurons from FAD mice expressing mutant human presenilin 1, PS1(M146L), mutant human amyloid precursor protein APP (Tg2576), and the double mutation of APP(Tg2576) and PS1(M146L). All three types of FAD mice demonstrated a loss of the integrity of the mitochondria at the synapse (where the nerve cells communicate with each other) and energy production in the brain. This work was highlighted in a Mayo Clinic Press Release and highlighted in an Alzheimer’s Disease Research News Update on March 5, 2012 (Cell Energy Dysfunction Is Present Early In Alzheimer's, Before Memory Loss AHAF-Funded Research May Lead To Future Detection Methods, Treatments http://www.ahaf.org/alzheimers/newsupdates/cell-energy-dysfunction-is.html ).
To further understand the role mitochondria play in AD, Dr. Trushina together with Dr. Poduslo’s team examined the effect of soluble and insoluble beta-amyloid (Abeta) peptides (both Abeta 40 and Abeta 42) on mitochondrial functions in nerve cells. Confirmation of Abeta binding and aggregation was done using a number of high-tech measurement and visualization methods, including electron microscopy, dynamic light scattering, atomic force microscopy and confocal microscopy. In non-disease neurons, addition of Abeta 40 and Abeta 42 slowed down mitochondrial trafficking in a dose-dependent manner with Abeta 42 exhibiting stronger inhibitions. Abeta peptides with higher propensity to aggregate (Abeta 39E 22) or Abeta fibrils affected mitochondrial motility to a greater extent than soluble peptides. Capture of soluble Abeta with a specific antibody or a reduction in Abeta plasma membrane binding rescued the problems with mitochondrial trafficking. Dr. Trushina’s and Poduslo’s teams have obtained data that suggests binding of Abeta to the plasma membrane is sufficient to inhibit mitochondrial trafficking regardless of the type of Abeta peptide. In the future, the team will determine the common signaling cascade involved in the mitochondrial trafficking inhibition that could help to identify the potential targets for therapeutic intervention of AD.
About the Researcher
First published on: April 26, 2011
Last modified on: July 18, 2016