ApoE-Tau axis in preeclampsia, a severe pregnancy complication, and neurodegeneration

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ABSTRACT Preeclampsia (PE) is a significant cause of maternal and fetal morbidity and mortality, affecting 5-8% of all pregnancies. This condition, characterized by de novo hypertension after 20 weeks of gestation and near term, along with proteinuria or other signs of end-organ damage, has a mechanistic heterogeneity. PE is associated with a high incidence of chronic diseases later in life, such as cardiovascular disease, diabetes mellitus, and renal disease. Our recent findings indicate that PE and Alzheimer's disease (AD) and related disorders (ADRD) share a common etiology involving proteinopathy/tauopathy and impaired autophagy. The accumulation of protein aggregates in the PE placenta is directly linked to dysregulated lysosomal biogenesis. Through primary human trophoblast assays, pre-clinical humanized PE mouse models, and predictive and therapeutic approaches, we have validated the proteinopathy/tauopathy etiology of PE. Preliminary data suggest that PE serum can accelerate tau induction and aggregation in human Tau transgenic mice by 4 months of age, and that the PE inhibitor, non-mammalian disaccharide trehalose, can reverse these effects. However, there are still significant gaps in our understanding of the upstream triggers of tauopathy/proteinopathy in PE and AD. Abnormal lipid metabolism is proposed as a critical factor in both conditions. Apolipoprotein E (ApoE) is crucial for the uptake and clearance of atherogenic lipoproteins, and its polymorphic alleles are implicated in PE and AD pathologies. ApoE alleles also regulate tauopathy and contribute to neurodegeneration. We hypothesize that the ApoE-tau axis plays a vital role in the proteinopathy/tauopathy-dependent progression of PE and associated dementia. To investigate this, we propose using ApoE2, ApoE3, and ApoE4 knock-in mice from MODEL-AD to study the onset of PE-associated chronic diseases, particularly the progression of synaptic dysfunction and memory deficits associated with AD- like progression in mice treated with serum or exosomes from PE patients. Our specific aims are: 1) Assess pregnant ApoE knock-in mice for induction of PE-like features in response to PE serum or exosomes, 2) Confirm the onset of tau protein induction and aggregation in ApoE mice challenged with PE serum or exosomes & 3) Evaluate human ApoE knock-in mice for induction of AD-like features in response to serum or exosomes from PE patients. This proposal is supported by strong preliminary results and relevant experimental strategies. These studies in a well-defined humanized pre-clinical model align with our overarching goal of understanding the PE-AD connection and may provide a basis for clinical intervention.