Current Research — Zipfel Lab
Vascular Contributors to Dementia/
Cerebral Amyloid Angiopathy
Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid-β (Aβ) peptide within the walls of cerebral vessels. CAA has long been connected to cerebral hemorrhage and, more recently, has been placed as a substantial risk factor for ischemic brain injury and progressive cognitive impairment in Alzheimer's disease. Using genetically manipulated mice that overexpress human Aβ and an in vivo cranial window preparation with fluorescent and video microscopy, we have found that both soluble and fibrillar forms of Aβ directly influence cerebrovascular function. Moreover, certain Aβ-mediated cerebrovascular effects appear reversible, as acute administration of γ-secretase inhibitors was observed to reduce soluble Aβ-mediated vascular dysfunction. Our past work shows CAA causes severe, dose-dependent cerebrovascular vasomotor impairment. CAA-induced cerebrovascular vasomotor impairment increases susceptibility to ischemic brain injury after stroke. We also found that NADPH oxidase-derived reactive oxygen species play a causal role in the cerebrovascular vasomotor impairment caused by the CAA. We found that inhibition of NADPH oxidase dramatically (by 80%) reduces the CAA formation in aged APP mice. We are currently extending these observations by examining the roles of NADPH oxidases and heparan sulfate proteoglycans as a cell surface initiator of Aβ-induced NADPH oxidase activation, vascular oxidative stress, and vascular smooth muscle cell dysfunction. We hypothesized Apolipoprotein E (ApoE) as a potential downstream effector through which NADPH oxidase-derived reactive oxygen species contribute to CAA formation. Through these studies, we hope to define the molecular underpinnings of CAA-induced cerebrovascular dysfunction and ultimately develop new strategies toward which the ischemic and cognitive effects of CAA can be prevented and/or reduced.
Aneurysmal Subarachnoid Hemorrhage
Aneurysmal subarachnoid hemorrhage (SAH), caused by rupture of an intracranial aneurysm and extravasation of blood into the subarachnoid space, is associated with high morbidity and mortality. The devastating outcomes after SAH result primarily from secondary brain injury due to two processes – early brain injury and delayed cerebral ischemia. Multiple lab projects examine the pathophysiology underlying secondary brain injury after SAH. Our prior work demonstrated that "preconditioning" with hypoxia affords strong protection against post-SAH neurovascular dysfunction. Ongoing studies extend these observations to examine the molecular pathways underlying vascular and neuronal protection afforded by "preconditioning" and "postconditioning" approaches, and also assess the translational potential of a conditioning-based strategy to combat SAH-induced neurovascular dysfunction. Other areas of interest include determining the role of matrix metalloproteinase-9 and ATP-dependent potassium channels in early brain injury, vascular dysfunction and neuronal death after SAH. The overarching purpose of this work is to identify new molecular targets with therapeutic potential in preventing or reducing the devastating consequences of aneurysm rupture.
Dural Arteriovenous Fistulae
Dural arteriovenous fistulae (dAVF) are pathologic shunts between dural arteries and dural venous sinuses and leptomeningeal veins that make up 10%-15% of all intracranial vascular malformations. Because of the relative rarity of these malformations, few centers have an adequate number of patients to perform complex analyses of natural history or treatment. Dr Zipfel has collaborated with leading investigators in the field of dAVF research to form the consortium for dural arteriovenous fistula outcomes research (CONDOR), a collaboration with a pooled data registry of almost 2000 patients. This represents the largest data registry of dAVF patients in the world and will enable multiple future analyses to improve dAVF patient outcomes.