Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE41. APOE4 is a major genetic risk factor for Alzheimer’s disease2, 3 and is associated with Down’s syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage3. Neurovascular dysfunction is present in normal APOE4 carriers4, 5, 6 and individuals withAPOE4-associated disorders3, 7, 8, 9, 10. In mice, lack of Apoe leads to blood–brain barrier (BBB) breakdown11, 12, whereas APOE4 increases BBB susceptibility to injury13. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.

LRP (low-density lipoprotein receptor-related protein) is linked to Alzheimer's disease (AD). Here, we report amyloid beta-peptide Abeta40 binds to immobilized LRP clusters II and IV with high affinity (Kd = 0.6-1.2 nM) compared to Abeta42 and mutant Abeta, and LRP-mediated Abeta brain capillary binding, endocytosis, and transcytosis across the mouse blood-brain barrier are substantially reduced by the high beta sheet content in Abeta and deletion of the receptor-associated protein gene. Despite low Abeta production in the brain, transgenic mice expressing low LRP-clearance mutant Abeta develop robust Abeta cerebral accumulations much earlier than Tg-2576 Abeta-overproducing mice. While Abeta does not affect LRP internalization and synthesis, it promotes proteasome-dependent LRP degradation in endothelium at concentrations > 1 microM, consistent with reduced brain capillary LRP levels in Abeta-accumulating transgenic mice, AD, and patients with cerebrovascular beta-amyloidosis. Thus, low-affinity LRP/Abeta interaction and/or Abeta-induced LRP loss at the BBB mediate brain accumulation of neurotoxic Abeta.

Low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears amyloid β-peptide (Aβ) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Aβ in humans. Recombinant LRP cluster IV (LRP-IV) bound Aβ in plasma in mice and in Alzheimer's disease-affected humans with compromised sLRPmediated Aβ binding, and reduced Aβ-related pathology and dysfunction in a mouse model of Alzheimer mice, suggesting LRP-IV can effectively replace native sLRP and clear Aβ.LRP binds the Alzheimer's disease neurotoxin, Aβ, at the abluminal side of the blood-brain barrier (BBB), which initiates Aβ clearance from brain to blood via transcytosis across the BBB1 -4. In the liver, LRP mediates systemic clearance of Aβ5. β-secretase cleaves the Nterminus extracellular domain of LRP6, which releases soluble LRP (sLRP). sLRP normally circulates in plasma 7 .Two major binding domains of LRP, cluster II and cluster IV 8 , bind Aβ in vitro with high affinity: i.e., Aβ40 > Aβ42 (ref. 2). We hypothesized that LRP recombinant cluster IV (LRP-IV) retains its high-affinity binding for Aβ in vivo, and that this binding alters Aβ transport at the BBB, which is dominated by the cell-surface LRP1 -4 and the receptor for advanced glycation end-products (RAGE) 9 , resulting in Aβ efflux from the brain. We also hypothesized

Abstract-Accumulation of amyloid ␤-peptide (A␤) in the central nervous system (CNS) may initiate pathogenic cascades mediating neurovascular and neuronal dysfunctions associated with the development of cerebral ␤-amyloidosis and cognitive decline in patients with Alzheimer disease (AD) and with related familial cerebrovascular disorders. Whether A␤-related pathology in the CNS is reversible or not and what key therapeutic targets are controlling A␤/amyloid levels in the aging brain remain debatable. In this article, we summarize recent evidence why the receptor for advanced glycation end products and low-density lipoprotein receptor related protein 1 in the vascular CNS barriers are critical for regulation of A␤ homeostasis in the CNS and how altered activities in these 2 receptors at the blood-brain barrier may contribute to the CNS A␤ accumulation resulting in neuroinflammation, disconnect between the cerebral blood flow and metabolism, altered synaptic transmission, neuronal injury, and amyloid deposition into parenchymal and neurovascular lesions. We briefly discuss the potential of advanced glycation end products and low-density lipoprotein receptor related protein 1-based therapeutic strategies to control brain A␤ in animal models of AD and ultimately in patients with AD and related familial cerebrovascular ␤-amyloidoses. Key Words: acute care Ⅲ Alzheimer disease Ⅲ amyloid ␤-protein Ⅲ blood-brain barrier C ontinuous removal of amyloid ␤-peptide (A␤) species from the central nervous system (CNS) is important for preventing their potentially neurotoxic accumulations in brain interstitial fluid (ISF). At the critical threshold concentrations in brain ISF, A␤ may initiate differential pathogenic cascades mediating neurovascular and neuronal stress and ultimately the development of cerebral and neurovascular ␤-amyloidosis and dementia in patients with Alzheimer disease (AD) and related A␤-disorders. A␤ is produced by almost all cells in peripheral tissues and by all types of cells in the CNS, but A␤'s physiological functions still remain unknown.There is little evidence that normal brain aging results in local overexpression of the A␤ precursor protein (APP) and overproduction of A␤. 1 A relatively small number of AD patients may have increased A␤ production in the CNS because of inherited mutations in the APP gene nearby the A␤ coding region (ie, Swedish mutation) or presenilins 1 or 2 genes. 2 However, the majority of patients with so-called nongenetic or late-onset AD and patients with familial forms of cerebrovascular ␤-amyloidoses do not have increased A␤ production or APP overexpression in the CNS. These patients likely exhibit a failure in A␤ clearance from the CNS because of either deficient transport efflux mechanisms for A␤ at the blood-brain barrier (BBB) 3,4 or its faulty degradation in the CNS. 5 Alternatively, an increased influx of circulating A␤ across the BBB may result in A␤ brain accumulation or its deposition in the CNS. 3,4,6 Regulation of A␤ levels in Brain ISF Normal A␤ concentrations in ...

Brain hemorrhage is a serious complication of tissue plasminogen activator (tPA) therapy for ischemic stroke. Here we report that activated protein C (APC), a plasma serine protease with systemic anticoagulant, anti-inflammatory and antiapoptotic activities, and direct vasculoprotective and neuroprotective activities, blocks tPA-mediated brain hemorrhage after transient brain ischemia and embolic stroke in rodents. We show that APC inhibits a pro-hemorrhagic tPA-induced, NF-kappaB-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium in vivo and in vitro by acting through protease-activated receptor 1. The present findings suggest that APC may improve thrombolytic therapy for stroke, in part, by reducing tPA-mediated hemorrhage.