Scott Heston

Introduction: Multiple processes are theorized to contribute to spontaneous Alzheimer’s Disease (AD). In vivo diagnosis of AD has only become possible in the last decade and requires several measurements including tau and beta-amyloid correlates¹. The newfound ability to diagnose AD pre mortem has enabled informed selection of study participants in a research setting, although it does not currently affect clinical outcomes. Sterile inflammation is a measurable proxy for AD etiology in cell-line investigation. Amidst this rapidly evolving and varied research environment, several mechanisms linked to AD pathophysiology that involve reverse transcription have been reported^2,3,4. Reverse transcription is any process that transcribes RNA into DNA and is mediated by a reverse transcriptase. A prominent class of reverse- transcription mediated mechanisms is long interspersed nuclear element 1 (LINE1). LINE-1 is a transposable element found in the human genome that encodes its own reverse transcriptases, known as ORF1/2. Methods: Human AD cell lines were manipulated with Crispr to knockdown L1 expression. Additionally, a murine model with elevated measures of L1 activity and neuroinflammation was treated with an antiretroviral inhibitor at human therapeutic levels. The efficacy of several reverse transcription inhibitors on ORF1/2 activity was also tested in a human cell line. Penetrance through the blood brain barrier of several FDA-approved reverse transcription inhibitors was tested in patients. Results: L1 knockdown lowered interferon levels and markers of age-related neuroinflammation². Antiretroviral inhibition significantly reduced IFN-I responses as measured by an ORF1 antibody, but not L1 expression or the presence of senescent cells². The expression of L1 mRNA was weakly downregulated, but in most cases did not reach statistical significance². In one clinical trial, drug levels of efavirenz, emtricitabine, and tenofovir were reduced approximately 200-fold, 2-fold, and 20-fold, respectively in the CSF relative to serum⁵. Conclusion: There exist several mechanisms by which a reverse- transcriptase mediated mechanism leads to neural aging. Although current pharmacology does not allow highly specific inhibition of individual mechanisms involving reverse transcription, Crispr permits more precise modulation in cell lines. Given the relatively few known positive effects of reverse transcription, it is hopeful that reverse transcription inhibition may play a role in the prevention of neural aging. Further research is needed to investigate the diversity of endogenous human reverse transcription and the potential role of reverse transcriptase inhibition in AD prevention.

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