Critical role of Presenilin 2 in myocardial integrity and functions, insights into ultrastructure, calcium handling and mitochondrial function.

Presenilin 2 (PS2), a protein best known to be part of the γ-secretase complex and mutated in familial Alzheimer’s disease (FAD), has also been proposed to exert important functions outside the nervous system. In particular, its role in Ca²⁺ handling, mitochondrial function, and cellular metabolism may extend beyond neurons and potentially influence cardiac physiology. The possibility that shared molecular pathways could underlie both neurodegenerative and cardiovascular conditions raises intriguing questions about the broader impact of PS2 dysfunction. This thesis aims to provide a comprehensive investigation into the role of PS2 and FAD-associated PS2 mutations in the regulation of cytosolic Ca²⁺ homeostasis and lipid droplet (LDs) dynamics, as well as their impact on myocardial ultrastructure. To explore the physiological and pathological roles of wild-type PS2 and its FAD-linked variants, four-month-old male mice of the following genotypes were utilized: C57BL/6J (WT), PS2 knockout (PS2KO), and FAD-PS2-N411I transgenic PS2.30H lines. The findings reveal that both the absence of PS2 and the presence of FAD-associated mutations induce marked alterations in myocardial ultrastructure. These include loss of sarcomeric organization, disruption of the interfibrillar mitochondrial network, and decoupling of the sarcoplasmic reticulum-mitochondria interface. Moreover, PS2 deficiency resulted in impaired Ca²⁺ cycling, while both PS2 loss and FAD mutations led to defects in cellular contractility. Notably, PS2KO hearts exhibited an increased number and size of LDs, suggesting a dysregulation in lipid metabolism in this organ. This LD accumulation is associated with potential bioenergetic dysfunction, which in turn may compromise Ca²⁺ handling and contractile capacity. These observations suggest that, although both PS2 deletion and FAD-mutation produce similar cardiac phenotypes, the underlying molecular mechanisms may differ and remain to be fully elucidated. Collectively, the data presented herein support the hypothesis that PS2 acts as a molecular mediator at the intersection of Alzheimer’s disease and cardiac dysfunction. Rather than offering definitive conclusions, this work highlights PS2 as a potential regulatory hub linking neurodegeneration and cardiovascular pathology via converging mechanisms involving Ca²⁺ homeostasis, mitochondrial integrity, and lipid metabolism. These findings warrant further investigation into PS2 role in cellular stress responses, metabolic adaptation, and tissue-specific vulnerability.