Targeted lipid-siRNA complexes for SPP1-silencing in Alzheimer's Disease

Vanderbilt University, Nashville TN

Investigators

Abstract

Project Summary: Alzheimer's Disease (AD) is a fatal neurodegenera�ve disorder characterized by progressive memory loss and execu�ve dysfunc�on. Recent research has highlighted the cri�cal role of inflamma�on in AD pathogenesis, with secreted phosphoprotein 1 (SPP1) iden�fied as a key driver of neuroinflamma�on. SPP1 levels are increased in both the cerebrospinal fluid and serum of AD pa�ents and are associated with faster cogni�ve decline. While global SPP1 knockout in mouse models of AD has been shown to decrease amyloid plaques and reduce neuroinflamma�on, the specific contribu�ons of SPP1 from different cellular sources, par�cularly perivascular cells, remain unclear. The primary objec�ve of this project is to develop novel siRNA delivery pla�orms to selec�vely target and knockdown SPP1 in perivascular cells, specifically border-associated macrophages (BAMs) and perivascular fibroblasts (PFBs), to elucidate their role in AD pathogenesis. This approach aims to address fundamental gaps in our understanding of how the spa�al origins and temporal expression paterns of SPP1 contribute to AD progression. In AIM 1, I will u�lize a first-genera�on lipid-siRNA conjugate (siRNA-L₂) to inves�gate the impact of perivascular SPP1 on AD progression. This will involve administering siRNA-L₂ targe�ng SPP1 at early (2 months) and mid (6 month) �mepoints in the 5xFAD mouse model of AD, followed by assessment of amyloid burden and neuroinflamma�on. In AIM 2, I will characterize novel siRNA-complex chemistries to op�mize cell-type specific delivery to BAMs and PFBs. The efficacy and specificity of these conjugates will be evaluated both in vitro and in vivo. This project leverages the specificity of siRNA technology and innova�ve delivery strategies to dissect the temporal and cell-specific contribu�ons of SPP1 to neuroinflamma�on in AD. Successful comple�on of this research will not only enhance our understanding of AD pathogenesis but also lay the groundwork for developing targeted interven�ons that can effec�vely modulate SPP1's impact on AD at the appropriate �me and loca�on. Moreover, the cell-type specific siRNA delivery pla�orms developed in this project could have broader applica�ons in inves�ga�ng and therapeu�cally targe�ng other key drivers of age-related neurodegenera�ve diseases.