of the proposed research In response to the NIH NOT-AG-20-008, the current Alzheimer?s Disease study pilot project administrative supplement application is to expand the parent R61 award entitled ?Repressing Retrotransposon LINE-1: New Concepts for Osteoarthritis Treatment?, which is not focused on Alzheimer?s disease and its related dementias (ADRD), to allow it to develop a focus on ADRD. As administrative supplements, the work proposed here is within the scope and a natural extension of the research of the R61. The R61 focuses on discovering mechanisms of aging and injury associated joint degenerative diseases and developing prevention and treatment strategies for such degenerative diseases. During this process, we found common pathological mechanisms shared by both skeletal and neural degenerative diseases during aging, in particular between aging-associated osteoarthritis (OA) and ADRD. Recent evidence indicate that de-repression of retrotransposon LINE-1 or L1, which accounts for 17 percent of human genome, are involved in inflammation and degeneration of both cartilage joint and brain tissues during aging. Thus, the methodologies we have developed to study the relationship between L1 and cartilage joint degeneration can be used to determine the cause-effect relationship between L1 and ADRD. The innovative hypothesis is that, during aging-associated AD, the cellular content of L1 is 1) significantly increased in the brain and 2) responsible for stimulation of inflammation and A? accumulation that lead to neurodegeneration. If so, AD pathogenesis can be inhibited by repressing L1 using FDA-approved anti-viral drug nucleoside reverse transcriptase inhibitors (NRTIs). This hypothesis will be tested through two aims.
The first aim i s to characterize aging induced L1 de-repression in an AD transgenic mouse model. It will establish whether early-onset of AD would result in de-repression of the L1 levels in mouse brain.
The second aim i s to determine whether NRTIs inhibit AD pathogenesis by repressing L1 levels in AD animal models in vivo. NRTI nucleoside cytidine analogue Lamivudine will be tested for its ability of inhibiting neurodegeneration in AD transgenic mice. It will establish the efficacy and the window of intervention for NRTI to modify neurodegeneration in AD animal models in vivo. If successful, NRTIs, which are readily available, may be re-purposed for AD treatment in human. It will not only change the concepts that drive the AD research field, but also impact the clinical practice of how we treat AD patients.
The proposed research is relevant to public health because the newly gained knowledge may lead to development of so-called ?senostatic? drugs as a novel approach for AD treatment. The re-purpose of the NRTIs for AD treatment is highly attractive because it will greatly shorten the length and expense of AD drug development. Thus, the proposed research is relevant to the part of NIH's mission that translating scientific discovery into health that will help to reduce the burdens of human disability.