Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein

Abstract

Alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated in the mechanisms of Alzheimer's disease (AD), but their role in the amyloid deposition and cognitive impairment associated with AD remains unclear. We used mice overexpressing the Swedish mutation of the amyloid precursor protein (Tg2576) as a model of AD to examine the role of reactive oxygen species produced by NADPH oxidase in the cerebrovascular alterations, amyloid deposition, and behavioral deficits observed in these mice. We found that 12-to 15-month-old Tg2576 mice lacking the catalytic subunit Nox2 of NADPH oxidase do not develop oxidative stress, cerebrovascular dysfunction, or behavioral deficits. These improvements occurred without reductions in brain amyloid-␤ peptide (A␤) levels or amyloid plaques. The findings unveil a previously unrecognized role of Nox2-derived radicals in the behavioral deficits of Tg2576 mice and provide a link between the neurovascular dysfunction and cognitive decline associated with amyloid pathology.Alzheimer's disease ͉ cerebral blood flow ͉ tg2576 T he amyloid-␤ peptide (A␤) is central to the pathogenesis of Alzheimer's disease (AD), the most common form of dementia in the elderly (1). A␤ peptides are cleaved from the amyloid precursor protein (APP) by two aspartyl proteases, termed ␤-and ␥-secretases, and form deposits in the brain parenchyma (amyloid plaques) and around blood vessels (amyloid angiopathy) (2). The mechanisms by which A␤ leads to cognitive impairment have not been completely elucidated, although recent evidence suggests that small aggregates of A␤ may be key pathogenic factors by disrupting synaptic function and inducing neuronal death (2).However, A␤ also exerts powerful effects on cerebral blood vessels (3). In vitro and in vivo studies have demonstrated that A␤ enhances vasoconstriction, impairs responses to vasodilators, and reduces cerebral blood flow (CBF) (4, 5). In addition, transgenic mice overexpressing APP and A␤ have major alterations in resting CBF and in key cerebrovascular control mechanisms (5-9). For example, the increase in CBF induced by neural activity (functional hyperemia), a response that matches the brain's energy demands with its blood supply, and the ability of cerebral endothelial cells to regulate CBF are profoundly impaired in mice overexpressing APP (7, 10). The vasoconstriction induced by A␤ may underlie the marked reductions in CBF observed in the early stages of AD (11). The harmful cerebrovascular effects of A␤, in concert with epidemiological and pathological findings linking AD with cerebrovascular diseases (12-16), have suggested that A␤ has deleterious actions both on neurons and cerebral blood vessels, which may act synergistically to induce brain dysfunction in AD (3,17).The cerebrovascular alterations observed in mice overexpressing APP are associated with vascular oxidative stress and are counteracted by free radical scavengers (6,18,19), implicating reactive oxygen species (ROS) in the dysfunction. A major source...

Neurovascular function in Alzheimer's disease patients and experimental models

“…Hence, eliminating O 2 KÀ can restore cerebrovascular function and prevent a self-perpetuating cycle of oxidative damage. Remarkably, and as a testament to the reversibility of this process, cerebrovascular rescue has been achieved even in aged APP mice (12 to 16 months old) after genetic (Park et al, 2008) or pharmacological interventions with antioxidants . The The above evidence suggests that cerebrovascular dysfunction in young APP mice lacking CAA is due to a free radical cascade triggered by soluble Ab (Figure 2A).…”

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

“…These observations indicate that CD36 deletion counteracts the cerebrovascular dysfunction in Tg2576 mice even at an advanced age. Accumulation of Aβ in cerebral blood vessels plays an important role in the neurovascular dysfunction of aged Tg2576 mice (20,27). Consequently, we examined whether the rescue in neurovascular and vasomotor function observed in aged Tg2576 mice could be related to reduction in vascular amyloid deposition.…”

“…Finally, we used a two-trial spatial-memory task in a Y maze (20,33,34) to determine whether the reduced neurovascular dysfunction and CAA in Tg2576/CD36 0/0 mice are associated with improved cognitive performance. We chose the Y maze test for its high sensitivity to the behavioral dysfunction of Tg2576 mice (35).…”

“…Converging evidence indicates that Aβ exerts its deleterious vascular effects by producing reactive oxygen species (ROS) (11, 15, 16) through the enzyme NADPH oxidase (17)(18)(19)(20). A key signaling pathway through which Aβ activates NADPH oxidase in cerebral blood vessels involves CD36 (21), a critical innate immunity receptor that binds Aβ and is present in endothelial cells and microglia/macrophages (22, 23).…”

Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging

“…Vascular dysregulation in AD includes deficiencies in cerebrovascular reactivity, CBF, and neurovascular coupling responses (Girouard and Iadecola 2006;Gorelick et al 2011;Hock et al 1997;Rombouts et al 2000). Neurovascular coupling dysfunction of AD has been replicated in experimental studies showing that in mouse models of AD, neurovascular coupling is also significantly impaired (Rancillac et al 2012;Shin et al 2007;Royea et al 2017), at least in part, due to enhanced oxidative stress (Nicolakakis et al 2008;Park et al 2008;Park et al 2005) arising from mitochondrial dysfunction and inflammation (Lacoste et al 2013;Ongali et al 2014). Importantly, recent evidence suggests that pharmacological interventions that rescue functional hyperemia result in improved cognitive function in mice with AD pathologies (Tong et al 2012;Nicolakakis et al 2008).…”