Targeting the ANG/TIE2 pathway to treat Alzheimer's disease and related dementias - PROJECT SUMMARY Clinical trials for Alzheimer’s disease and related dementias (ADRDs) have had only limited success in treating dementia. Growing evidence suggests that a major contributor to many ADRDs is blood brain barrier (BBB) compromise and cerebrovascular dysfunction. The overarching aim of this proposal is to test whether BBB compromise and cerebrovascular dysfunction can be prevented by targeting the Angiopoietin/TIE2 (ANG/TIE2) pathway. The ANG/TIE2 pathway is a key regulator of BBB integrity. Angiopoietin-1 (ANGPT1) binds the receptor TEK tyrosine kinase (TIE2), which results in TIE2 phosphorylation (phospho-TIE2, p-TIE2) and activation. Activated p-TIE2 modulates BBB integrity through increasing tight junction proteins. Conversely, binding of Angiopoietin-2 (ANGPT2) to TIE2 prevents phosphorylation and activation, resulting in decreased BBB integrity. Vascular Endothelial Protein Tyrosine Phosphatase (VE-PTP) prevents phosphorylation of TIE2, thus inducing inflammation-induced vascular permeability. Studies have shown that targeting the ANG/TIE2 pathway improves vascular health in pulmonary arterial hypertension, microvascular thrombus formation in sepsis, and diabetic retinopathy. However, no studies have investigated a direct link between the ANG/TIE2 pathway and BBB integrity in ADRDs. Therefore, we will test our hypothesis that manipulating the ANG/TIE2 pathway will preserve BBB integrity and cerebrovascular function in ADRDs. We will use the novel wild-derived WSB.APP/PS1 mouse model, which develops hallmarks of ADRDs including parenchymal plaque deposition, cerebral amyloid angiopathy, neuroinflammation, neurodegeneration, and cognitive deficits. In Aim 1, we will test the hypothesis that decreasing ANGPT2 levels will increase p-TIE2, strengthen tight junctions, and stabilize the BBB—thereby preventing cerebrovascular damage. We will create cohorts of WSB.APP/PS1 and WSB (no amyloid control) mice heterozygous for Angpt2 (Angpt2+/-), which will age to 4 (plaque onset) and 8 months (overt ADRD phenotypes). At these timepoints, we will assess cognition, cerebrovascular integrity, amyloid deposition, neurodegeneration, and neuroinflammation using a battery of in vivo and postmortem assays—including novel spatial recognition, positron emission tomography/computed tomography (PET/CT), vascular leakage, biochemistry, and immunohistochemistry. In Aim 2, we will test the hypothesis that treating WSB.APP/PS1 mice with the VE-PTP inhibitor AKB-9778 will also increase p-TIE2 and stabilize BBB function— thereby reducing ADRD phenotypes. To test this, we will follow a robust preclinical pipeline developed by the Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) consortium. After determining the dosing regimen through pharmacokinetic modelling, WSB.APP/PS1 and WSB control mice will be dosed with AKB-9778 from 4 to 8 months, and phenotypes will be assessed using the same assays described in Aim 1. Collectively, our synergistc genetic and pharmacological approach extensively evaluates the potential for targeting the ANG/TIE2 pathway to prevent and/or treat ADRDs.
