- B.S. Biology with an emphasis on Biochemistry, Northwest Missouri State University, Maryville, MO
As one of the most feared and devastating neurodegenerative diseases, Alzheimer’s Disease (AD) currently affects 35 million people worldwide; a number that is predicted to triple by 2050. As the reversal of clinically present AD is unlikely, it is imperative that we as researchers identify risk mechanisms that would allow physicians to intervene in the preclinical phase of AD.
Clusterin (CLU), or Apolipoprotein J, is a heterodimeric apolipoprotein that is highly expressed in ovary, testis, and brain. Of particular interest, CLU has been shown to facilitate the transport of amyloid beta across the BBB, regulate inflammation and apoptosis, and reduce Aβ aggregation and toxicity indicating that CLU confers some level of neuroprotection. Recently, two independent Genome Wide Association Studies (GWAS) have demonstrated a strong association between CLU polymorphisms and the development of late-onset AD (LOAD). Moreover, recent studies have shown increased CLU in AD brain; however, decreased CLU has been associated with both aging and CLU gene variants. Despite these clinical findings, the neurophysiological role of CLU and the AD-risk mechanisms underlying CLU gene polymorphism are largely unknown. A recent pilot study performed in normally ageing mice indicates that CLU expression is significantly down-regulated in specifically in the female brain during the transition from pre- to peri-menopause. This indicates that major hormonal alterations in female brain have a significant impact on CLU levels. Furthermore, these data indicate a general decrease in mitochondrial bioenergetics and a simultaneous increase in amyloid imbalance with a central factor being the interaction between CLU and insulin-like growth factor 1 (IGF-1) signaling.
As women are at a significantly higher risk for developing AD and CLU levels are considerably down-regulated following hormonal alterations, my research aims to determine how the triad of sex and sex hormones, brain CLU, and energy metabolism regulate each other in the pre-clinical phase of LOAD. These studies will provide a basis for development of sex-specific targeted therapies that could delay or prevent the onset of LOAD.