Sunday, May 11, 2025
5/11/2025
Roles of Periodontal Bacteria-Derived Dihydroceramides in Alzheimer's Disease - ABSTRACT. Over 5.4 million people worldwide have Down syndrome (DS), which is caused by trisomy of chromosome 21 (Chr21). Emerging DS studies demonstrate that Chr21 trisomy is associated with the overexpression of amyloid precursor protein (APP). The pathogenic alteration of APP cleavage positively correlates with the accumulation of Amyloid betta 40/42 (Aβ40/42) peptides, the hallmark of Alzheimer’s disease (AD), in most aged individuals with DS. In addition, it was also reported that patients with DS demonstrate elevated oral bacterial dysbiosis and periodontitis. However, our knowledge about the influence of virulent factors produced by P. gingivalis on AD in individuals with DS remains limited. Therefore, studies proposed in the Administrative supplement will investigate novel pathogenic host-bacterial interaction in experimental models of DS, of which age-associated AD pathogenic amyloidogenesis emerges with PGDHC. In addition, this study will help PI to establish novel collaborative relationships with AD- and DS-established investigators. We recently reported that a structurally unique P. gingivalis-derived isoC17:0-dihydroceramide-1-phosphoglycerol (PGDHC) exacerbates bone loss in experimental models of inflammatory osteolysis. Furthermore, our group also demonstrated that PGDHC enters the circulation as well as accumulates in the brain and elevates the production of Aβ. Using the parent K02 award, we generated new preliminary data demonstrating that 1) PGDHC is elevated age-associated periodontitis in wild-type mice; 2) PGDHC is frequently detected in post-mortem AD brains; 3) PGDHC-mediated periodontitis exacerbates Aβ42 accumulation in the brain of AD-like mice. We hypothesize that within the context of DS, a novel class of PGDHC produced by the critical periodontal pathogen P. gingivalis is engaged in pathogenic age-associated amyloidogenesis of APP. Our unique expertise in oral pathology, DS and AD demonstrates that we are ideally suited to test this hypothesis. We will elucidate the effects of PGDHC- mediated periodontitis on pathogenic amyloidogenic processing of APP and accumulation of Aβ in the mouse brain of DS mice, e.g. Ts65Dn, Dp1Yey, and corresponding wild-type control mice (both sexes). To further identify DS-associated molecular mechanisms of amyloid pathology in response to PGDHC, collected mouse brains will be analyzed by GeoMx™ Digital Spatial Profiler. Proposed studies will provide critical information on whether unique PGDHC exacerbates pathogenic amyloidogenesis of APP using experimental models of DS. This study is also expected to lay the foundation for future NIH applications, e.g., R01-INCLUDE and K99/R00 to promote diversity. Altogether, proposed emerging study meets the Component 1 scope of the INCLUDE: Targeted high-risk - high-reward basic science studies in areas highly relevant to Down syndrome and only achieved by the additional funding from an administrative supplement to the parent K02 award.
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