Alzheimer's Disease and COVID-19 Pathogenic Overlap: Implications for Drug Repurposing.

As COVID-19 continues, a safe, cost-effective treatment strategy demands continued inquiry. Chronic neuroinflammatory disorders may appear to be of little relevance in this regard; often indolent and progressive disorders characterized by neuroinflammation (such as Alzheimer's disease (AD)) are fundamentally dissimilar in etiology and symptomology to COVID-19's rapid infectivity and pathology. However, the two disorders share extensive pathognomonic features, including at membrane, cytoplasmic, and extracellular levels, culminating in analogous immunogenic destruction of their respective organ parenchyma. We hypothesize that these mechanistic similarities may extent to therapeutic targets, namely that it is conceivable an agent against AD's immunopathy may have efficacy against COVID-19 and vice versa. It is notable that while extensively investigated, no agent has yet demonstrated significant therapeutic efficacy against AD's cognitive and memory declines. Yet this very failure has driven the development of numerous agents with strong mechanistic potential and clinical characteristics. Having already approved for clinical trials, these agents may be an expedient starting point in the urgent search for an effective COVID-19 therapy. Herein, we review the overlapping Alzheimer's/ COVID-19 targets and theorize several initial platforms.

Development and function of FOXP3+ regulators of immune responses.

The Forkhead Box P3 (FOXP3) protein is an essential transcription factor for the development and function of regulatory T cells (Tregs), involved in the maintenance of immunological tolerance. Although extensive research over the last decade has investigated the critical role of FOXP3+ cells in preserving immune homeostasis, our understanding of their specific functions remains limited. Therefore, unveiling the molecular mechanisms underpinning the up- and downstream transcriptional regulation of and by FOXP3 is crucial for developing Treg-targeted therapeutics. Dysfunctions in FOXP3+ Tregs have also been found to be inherent drivers of autoimmune disorders and have been shown to exhibit multifaceted functions in the context of cancer. Recent research suggests that these cells may also be involved in tissue-specific repair and regeneration. Herein, we summarize current understanding of the thymic-transcriptional regulatory landscape of FOXP3+ Tregs, their epigenetic modulators, and associated signaling pathways. Finally, we highlight the contributions of FOXP3 on the functional development of Tregs and reflect on the clinical implications in the context of pathological and physiological immune responses.

COVID-19 as a Risk Factor for Alzheimer's Disease.

Severe acute respiratory disease coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although a primarily respiratory disease, recent reports indicate that it also affects the central nervous system (CNS). Over 25% of COVID-19 patients report neurological symptoms such as memory loss, anosmia, hyposmia, confusion, and headaches. The neurological outcomes may be a result of viral entry into the CNS and/or resulting neuroinflammation, both of which underlie an elevated risk for Alzheimer's disease (AD). Herein, we ask: Is COVID-19 a risk factor for AD? To answer, we identify the literature and review mechanisms by which COVID-19-mediated neuroinflammation can contribute to the development of AD, evaluate the effects of acute versus chronic phases of infection, and lastly, discuss potential therapeutics to address the rising rates of COVID-19 neurological sequelae.

The NLRP3 Inflammasome in the Pathogenesis and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia. Although AD is one of the most socioeconomically devastating diseases confronting humanity, no "curative" disease modifying drug has been identified. Recent decades have witnessed repeated failures of drug trials and have called into question the utility of the amyloid hypothesis approach to AD therapeutics design. Accordingly, new neurochemical processes are being evaluated and explored as sources of alternative druggable targets. Among these newly identified targets, neuroinflammation is emerging as a front-runner, and within the realm of neuroinflammation, the inflammasome, particularly the NLRP3 complex, is garnering focussed attention. This review summarizes current data and approaches to understanding the role of the NLRP3 inflammasome in neuroinflammation and AD, and systematically identifies and evaluates multiple targets within the NLRP3 inflammasome cascade as putative drug targets.