PDE1 inhibition to prevent vascular senescence and associated dementia features

Non-atherosclerotic vascular disease is a main causal mechanism in neurocognitive disorders, notably in vascular dementia (VD). VD and its co-morbidities are one of the major health care problems with extensive social and financial impact in the aging population of economically developed countries. Currently there are no treatments for dementia/VD, and some forms can even be exacerbated by current therapies (e.g. cerebral amyloid angiopathy).

Building further on promising preclinical research results obtained in a previous collaboration investigating vascular aging and neurodegeneration, Erasmus MC and ITCI will together evaluate the effect of chronic inhibition of cyclic nucleotide phosphodiesterase 1 (PDE1inh) on neurocognitive problems and dementia characteristics caused by vascular and neuronal aging. As a secondary objective the effect on cardio-renal dysfunction, a major disabling co-morbidity in dementia patients, will be evaluated. This will take place in our in-house developed, recognized mouse models of aging-induced neurodegeneration and vascular disease. In addition mechanistic insight will be obtained by studying the role of PDE1-cAMP-cGMP signalling in 3 potential pathogenic pathways: brain lipid dysregulation, peripheral and central inflammation, and cellular senescence. To complete the translational potential of the project, studies to assess the role of PDE1 and other cAMP/cGMP modulating mechanisms in arterial motor function in tissue from healthy, young and diseased, aged humans will be included. As we will use a clinically applicable PDE1inh that is currently being tested in a Phase II study in patients with idiopathic Parkinson’s Disease, finding an effect on vascular disease-related cognitive dysfunction in the present project might lead to direct translation into clinical studies in a subsequent, future project. Thus, this project can have important impact.