Cerebrovascular mitochondria as mediators of neuroinflammation in Alzheimer's Disease - ABSTRACT In Alzheimer’s Disease (AD), and to a lesser extent in non-demented individuals, deposition of amyloid β (Aβ) is found around cerebral vessels, a condition called Cerebral Amyloid Angiopathy (CAA). It is likely that the development of CAA, and consequently neurovascular unit (NVU) dysfunction, in AD may result from failure of Aβ clearance pathways. Importantly, all Aβ clearance pathways involve movement of Aβ towards the vasculature for elimination. Cerebrovascular endothelial cells (EC), which line all brain vessels, are the gatekeepers of the brain and are responsible for the maintenance of cerebral homeostasis through the blood-brain barrier (BBB). The development of CAA severely impacts brain health since it results in EC death, BBB breakdown, microhemorrhages, parenchymal Aβ accumulation, and is one of the earliest triggers for AD progression. EC dysfunction also affects other cells of the NVU, such as astrocytes or microglia, through finely regulated communication mechanism between these cells. Therefore, CAA-mediated EC dysfunction may also precipitate neuroinflammation in AD. Our preliminary data suggests that EC mitochondria serve as important sensors of Aβ damage. Previous studies have shown that mitochondria are responsible for the activation of inflammatory pathways through the release of mitochondrial danger associated molecular patterns (mtDAMPs), including mitochondrial reactive oxygen species (mtROS), due to formation of the pathological mitochondrial permeability transition pore (mPTP). Both cerebrovascular dysfunction and inflammation are shown early in disease pathogenesis, suggesting that early EC (and thus, BBB) dysfunction may drive and perpetuate AD pathology also by triggering widespread neuroinflammation. Here, we will test the hypothesis that Aβ induces mitochondrial dysfunction in cerebral ECs through deleterious alterations in mitochondria function (mtROS and mPTP opening) and that these alterations further contribute to neurovascular dysfunction and inflammation in CAA and AD. This proposal seeks to understand the role of alterations in cerebral EC mitochondrial health and bioenergetics, specifically focusing on the modulation of mtROS and mPTP, on human EC inflammatory activation due to Aβ (Aim 1; K99: Y1 and Y2). Moreover, we want to assess how Aβ-induced cerebral EC inflammatory mediators contribute to glial mitochondrial dysfunction and activation, through the modulation of mtDAMPs, using a human iPSC-derived glial cell cultures (Aim 2; K99: Y2 and R00: Y1). Finally, using an animal model of amyloidosis presenting CAA and gliosis (TgSwDI), we will test the hypothesis that Aβ-induced endothelial mtROS and mPTP mediate neuroinflammation and cognitive decline, by treating the animals with a mtROS scavenger or depleting their ECs of CypD, the main mPTP regulator (Aim 3; R00: Y1-Y3). The proposed experiments will provide a novel understanding of the role of vascular mitochondria as initiators of inflammation in AD and CAA, potentially resulting in the development of new disease modifying therapeutic strategies.
