Craig S. Atwood, PhD, University of Western Australia,1993 - US grants

Alzheimer's disease (AD) is a debilitating neurodegenerative disease that is characterized by neuronal cell loss and the deposition of protein aggregates. These neuropathological parameters are correlated with the presence of numerous markers of oxidative stress in the cell bodies of neurons suggesting the involvement of oxidative mechanisms in neuronal cell loss and/or protein deposition. Although the sources of the reactive oxygen species (ROS) leading to this oxidative stress have not been clarified, the brain responds to this chronic oxidative challenge by upregulating antioxidant defense systems (eg. increasing SOD1 and glutathione peroxidase expression). We now have three lines of evidence indicating that the increased generation of Abeta in AD also may be a compensatory response to oxidative stress that prevents neuronal apoptosis. Firstly, we have determined from in vitro studies that Abeta has significant antioxidant (superoxide dismutase) activity, secondly, that nanomolar concentrations of Abeta block apoptosis of neurons following trophic factor withdrawal, and thirdly that the Abeta amyloid burden of the AD-affected brain is significantly negatively correlated with oxidative stress markers. In support of these findings, we find fewer oxidative modifications in amyloid deposits and neurofibrillary tangles compared with the cell bodies of the neurons of AD-affected brains. Together, these compelling data provide a plausible physiological explanation for the increased generation of Abeta in AD and following head trauma. We hypothesize that as the disease progresses, the chronic overproduction of hydrogen peroxide by neuronal cells, microglia and Abeta amyloid deposits may overwhelm the antioxidant defense systems of the aging brain with the end result that ROS promote the apoptotic demise. Thus, the novel aspect of our hypothesis is the recognition that Abeta generation may be a form of pleiotrophic antagonism, whereby Abeta may be physiologically purposive under "normal" conditions (i.e. moderately increased concentrations of superoxide and/or high reducing equivalents), but may promote neuronal cell death under abnormal conditions (i.e. high concentrations of superoxide and Abeta that lead to excess hydrogen peroxide/low reducing equivalents). The proposed studies will therefore examine the generation of Abeta as a compensatory mechanism to oxidative stress that is both antioxidant and anti-apoptotic in nature while testing whether overwhelming oxidative challenges promote apoptosis. We also will test whether oxidative stress induces neurons to re-enter the cell cycle as a mechanism leading to cell death.

DESCRIPTION (provided by applicant): The central objective of the proposed research is to launch a new era of molecular genetics in a large national study of American adults, known as MIDUS (Midlife in the U.S.). Begun in 1995, MIDUS has become a major forum for multidisciplinary research on aging from early adulthood through later life, with a huge following from the scientific community (most frequently downloaded dataset at the national Archive of Computerized Data on Aging). Scientific productive from the study is extensive (about 400 publications), key themes of which clarify that the primary competitive advantage of MIDUS for molecular genetics is its comprehensive and cumulative assessments of environmental exposures. We will focus on two key exposures, socioeconomic status (SES) and social relationships (SR), which constitute well established influences on morbidity and mortality from social epidemiology. We build our specific aims around an explicit gene by environment approach to three outcomes: emotional distress, cognition, and inflammation. In each (Aims 1 through 3), we target primary genetic markers (i.e., those receiving the lion's share of attention in prior research as well as those for which there are functional rationales with regard to underlying neurobiological mechanisms) and examine the role of SES and SR environmental exposures as moderators of their influence on outcomes. Incorporating both risk and protective moderators, we will focus on cumulative SES disadvantage and cumulative SR advantage. An additional set of provisional genetic markers will also be included as supplemental analyses. The proposed work will be carried out with members of the MIDUS Refresher sample (newly recruited respondents) and the existing longitudinal sample (projected sample size for testing key gene by environment hypotheses is 5,400 adults). Embedded within MIDUS is also a national sample of twins for which additional gene by environment analyses will be conducted as well as analyses guided by a co-twin control design. A final aim of the proposed research is to create a genetic repository from the saliva-based DNA extraction and to then hold workshops in the final two years of the grant drawing on scientists from around the country to discuss plans to optimally leverage the use of this repository in a national study with unprecedented depth in assessment of diverse environmental exposures, only two of which are investigated in the proposed research. Overall, the future scientific inquiry that will emanate from the proposed plans to bring molecular genetics to MIDUS is of exceptional scope.

Project Summary This project aims to re-purpose the safe and well-tolerated gonadotropin-releasing hormone (GnRH) analogue Lupron for use in Alzheimer's Disease (AD). Lupron is currently FDA-approved for prostate cancer, endometriosis and uterine fibroids in adults and for central precocious puberty in children. We propose to confirm and extend results from a prior phase II study (Bowen et al, 2015) that demonstrated that Lupron halted cognitive and functional decline in a subgroup of women with mild-moderate AD who were also taking an acetylcholinesterase inhibitor (AChEI). Our objectives are to replicate, in the same subgroup, Lupron's clinical EFFICACY in this prior trial and to add neuroimaging and plasma BIOMARKERS that will help elucidate Lupron's likely multiple mechanisms of action in AD. These mechanisms include decreasing levels of Luteinizing Hormone (LH) based on extensive preclinical evidence that decreasing LH preserves cognition and decreases amyloid deposition and tau phosphorylation in animal models of AD, as well as new evidence that GnRH analogues may have important anti-inflammatory effects. We will (1) Conduct a three site, double-blind, randomized trial of Lupron (22.5 mg/12 weeks) compared with placebo to evaluate the changes over 48 weeks in cognition and function in women with mild-moderate AD who are also taking a stable dose of AChEI. We hypothesize that patients taking Lupron + AChEI will show a smaller pre- to post-treatment decline in cognition and function when compared to patients taking placebo + AChEI. (2) We will assess Lupron?s effect on structural and functional (ASL-MRI) neuroimaging biomarkers of AD. We hypothesize that patients who receive Lupron + AChEI will demonstrate less atrophy in AD-related brain regions and preserved hippocampal perfusion as compared to those who receive placebo + AChEI. (3) We will assess changes in plasma markers of inflammation. We hypothesize that patients taking Lupron + AChEI, as compared to those taking placebo + AChEI, will show decreased plasma pro-inflammatory cytokines. If this second phase II trial of Lupron + AChEI for AD is positive we will proceed to a phase III trial with the goal of gaining FDA approval for this novel combination therapy for AD. By re-purposing an existing medication, in combination with a current AD treatment, we will be able to build upon extensive previous research and development efforts, reducing the time frame and costs of making this promising therapy available to patients with AD. Results from this project have the potential for significant, near term clinical impact in patients currently suffering from or at risk of AD.