Naturally occurring modifiers of Alzheimer’s Disease

Alzheimer’s disease (AD) currently affects 5 million individuals in the US over the age of 65, with the affected population projected to increase to 14 million by 2050. Although familial AD is caused by rare and highly penetrant mutations in one of three genes (amyloid precursor protein, presenilin 1 and presenilin 2), over 90% of AD cases are sporadic, arising later in life. Despite the non-mendelian nature of LOAD, there is a significant genetic predisposition to the disease, and thus far, over 20 genetic risk factors (including ApoE4) have been identified through international genome-wide-association studies. Although significant progress has been made identifying risk factors, the majority are still unaccounted for, likely due to numerous small contributions to heritability by several genes, making them difficult to find in heterogeneous human populations.

Flies have emerged as a powerful model organism with which to study a variety of neurodegenerative diseases. They exhibit significant conservation of cellular processes with humans, including those implicated in LOAD such as immune response, inflammation, and lipid metabolism, and nearly 70% of human disease-causing genes have an orthologue in Drosophila. By leveraging the statistical power, environmental control and repeated measures afforded by Drosophila studies, our goal is to identify and validate genes and putative risk factors associated with LOAD in humans.

Mitochondrial DNA depletion and innate immunity in aging and disease

Aging is the primary risk factor for a number of diseases including cancer, diabetes, cardiovascular disease, and neurodegenerative diseases. Identification of mechansims that underlie aging and how these mechanisms affect susceptibility to neurodegeneration is central to being able to identify potential therapeutic targets and to increase the cognitively healthy years of a long lifespan. In particular, mitochondrial function has long been tied to the aging process with the oldest theory of aging positing that mitochondrial function underlies organismal aging. More recently however, age-related changes to the innate immune system have been implicated as a driving force in organismal aging and susceptibility to disease. The innate immune response becomes dysregulated with age, leading to a low-grade, chronic inflammatory state known as inflammaging, and an attenuated immune response to exogenous insults – immunosenesence. COVID-19 is just one of the most recent examples of a disease that is thought to affect the aging population because of dysregulated responses by the aging immune system.

Mitochondria play a central and well-characterized role in energy production and cellular metabolism. However, accumulating evidence has shown that mitochondria may also act as a signaling hub to modulate innate immunity. Dysregulation of mitochondrial function results in a loss of mitochondrial membrane potential, leading to release of a variety of components from the mitochondria into the cytosol. Although mitochondrial function and innate immune signaling clearly change with age, the exact mechanisms by which cells signal mitochondrial dysfunction and initiate a systemic immune response are still being uncovered. Data from our lab and others show that depletion of mtDNA copy number is one manipulation that can potentiate innate immune signaling in mice and flies (West et al, Nature 2015, unpublished results). We are interested in using a model of mtDNA depletion caused by expression of the mtDNAse UL12.5 to investigate the mechanisms by which mtDNA depletion is sensed by cells, the signaling pathways that lead to increased innate immune signaling in response to mtDNA depletion, and the effects hyperactive innate immune signaling has on lifespan and susceptibility to neurodegeneration.