MitoAD

Mitochondrial dysfunction has been hypothesized to be the primary event in Alzheimer's disease (AD) pathology.
Extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles are histopathological hallmarks of
the disease. The so called mitochondrial cascade hypothesis proposes that mitochondrial dysfunction is the
primary event in AD pathology. Numerous experiments demonstrated that accumulation of Aß in mitochondria
begins before the occurrence of extracellular deposition, and this leads to mitochondrial dysfunction with
increased oxidative stress, impaired mitodynamics and decrease in ATP production that leads to synaptic
dysfunction, apoptosis, and neurodegeneration.
Few mitochondrial enzymes are closely linked to the degradation of accumulated intra-mitochondrial Aß, but also to degradation of the mitochondrial targeting sequences that are cleaved off from the imported precursor proteins by the mitochondrial matrix peptidase. If these peptides fail to be cleared from the mitochondrial matrix, they may act as detergent-like, toxic agents, forming pores in the membranes.

This project stems from preliminary, original observations from mouse models, yeast KO models, and a screening of a gene encoding a mitochondrial protease in small cohorts of patients with neurodegenerative disorders.
In summary, this MitoAD project will be focused on trying to answer to the following question:
Are there variants in mitochondrial protease genes associated with increased risk for AD?

We have already selected 7 genes, and we will compare the frequency of: 1)Loss of function variants and 2)Missense variants with frequency <1% in the ADRD database vs. GnomAD database.
In case of significant differences in this first analysis, we will then possibly subdivide the ADRD cohort in two groups, i.e. AD and FTD, in order to see if the observed mitochondrial impairment is directly linked to AD/ Aß accumulation or is a more general defect, not specifically associated with neurodegeneration.

Mitochondrial dysfunction has been hypothesized to be the primary event in Alzheimer's disease (AD) pathology. Extracellular amyloid-beta (Aß) deposition is the key histopathological hallmark of AD, but Aß accumulation occurs also in mitochondria causing impairment in different mitochondrial pathways.
Diverse mitochondrial enzymes have a role in degradation of unfolded proteins including accumulated intramitochondrial Aß.
The scope of this project is to better define the role of these mitochondrial proteases on Aß processing and to evaluate how/if impairment in this pathway is linked to AD development.

We want to exploit the ADRD database to evaluate if variants in selected genes encoding mitochondrial proteases are indeed associated with increased risk for AD (and, in case, if this risk is specific for AD or is common to other dementia neurodegenerative conditions).