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The amyloid [beta]-protein precursor (A[beta]PP) is best known as the parent molecule to the amyloid [beta]-peptide that accumulates in the brains of patients with Alzheimer's disease. Secreted isoforms of A[beta]PP that contain the Kunitz proteinase inhibitor domain are analogous to the previously identified cell-secreted proteinase inhibitor known as protease nexin-2 (PN2). Although PN2/A[beta]PP is enriched in brain and in circulating blood platelets, little is understood of its physiological function and potential role in disease processes outside of amyloid [beta]-peptide generation. We hypothesized that the potent inhibition of certain procoagulant proteinases by PN2/A[beta]PP, coupled with its abundance in platelets and brain, indicate that it may function to regulate cerebral thrombosis. Here we show that specific and modest 2-fold overexpression of PN2/A[beta]PP in circulating platelets of transgenic mice caused a marked inhibition of thrombosis in vivo. In contrast, deletion of PN2/A[beta]PP in A[beta]PP gene knockout mice resulted in a significant increase in thrombosis. Similarly, platelet PN2/A[beta]PP transgenic mice developed larger hematomas in experimental intracerebral hemorrhage, whereas A[beta]PP gene knockout mice exhibited reduced hemorrhage size. These findings indicate that PN2/A[beta]PP plays a significant role in regulating cerebral thrombosis and that modest increases in this protein can profoundly enhance cerebral hemorrhage. Alzheimer's disease | hemorrhage | proteinase inhibitor

Objective Growing evidence indicates that the activation of c-Jun N-terminal kinase (JNK) is implicated in the multiple major pathological features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease-modifying therapeutic effect of systemic administration of SP600125, a small-molecule JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. Methods Using behavioral, histological, and biochemical methods, outcomes of SP600125 treatment on neuropathology and cognitive deficits were studied in APPswe/PS1dE9 mice. Results Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 weeks potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic reduction in amyloid plaque burden, β-amyloid production, tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, we found that SP600125 treatment strongly promoted nonamyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. Interpretation Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD. Ann Neurol 2015;77:637-654 [ABSTRACT FROM AUTHOR]

The aggregation of soluble amyloid-beta (Aβ) peptide into oligomers/fibrils is one of the key pathological features in Alzheimer's disease (AD). The Aβ aggregates are considered to play a pivotal role in the pathogenesis of AD. Therefore, inhibiting Aβ aggregation and destabilizing preformed Aβ fibrils would be an attractive therapeutic target for prevention and treatment of AD. S14G-humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to be a strong neuroprotective agent against various AD-related insults. Recent studies have shown that HNG can significantly improve cognitive deficits and reduce insoluble Aβ levels as well as amyloid plaque burden without affecting amyloid precursor protein processing and Aβ production in transgenic AD models. However, the potential mechanisms by which HNG reduces Aβ-related pathology in vivo remain obscure. In the present study, we found that HNG could significantly inhibit monomeric Aβ1-42 aggregation into fibrils and destabilize preformed Aβ1-42 fibrils in a concentration-dependent manner by Thioflavin T fluorescence assay. In transmission electron microscope study, we observed that HNG was effective in inhibiting Aβ1-42 fibril formation and disrupting preformed Aβ1-42 fibrils, exhibiting various types of amorphous aggregates without identifiable Aβ fibrils. Furthermore, HNG-treated monomeric or fibrillar Aβ1-42 was found to significantly reduce Aβ1-42-mediated cytotoxic effects on PC12 cells in a dose-dependent manner by MTT assay. Collectively, our results demonstrate for the first time that HNG not only inhibits Aβ1-42 fibril formation but also disaggregates preformed Aβ1-42 fibrils, which provides the novel evidence that HNG may have anti-Aβ aggregation and fibrillogenesis, and fibril-destabilizing properties. Together with previous studies, we concluded that HNG may have promising therapeutic potential as a multitarget agent for the prevention and/or treatment of AD. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Cerebral amyloid-beta protein (Aβ) deposition and associated neuroinflammation and apoptosis are increasingly recognized as an important component leading to cognitive impairment in Alzheimer’s disease (AD). Humanin (HN) and its derivative, S14G-HN (HNG), are best known for their ability to suppress neuronal death induced by AD-related insults in vitro. Furthermore, limited in vivo studies show that HNG can ameliorate memory impairment induced by intracerebroventricular injection of anti-cholinergic drugs or Aβ25-35. However, the mechanism underlying the in vivo effect remains unclear. In this study, we sought to determine the effects of HNG on neuroinflammatory responses and apoptosis associated with behavioral deficits induced by Aβ25-35 in vivo. Our results indicate that intracerebroventricular injection of aggregated Aβ25-35 induced impairment of learning and memory, markedly elevated numbers of reactive astrocytes, activated microglia, and apoptotic cells, as well as remarkable increased levels of IL-6 and TNFα. Moreover, intraperitoneal HNG treatment ameliorated behavioral deficits, and reduced neuroinflammatory responses and apoptotic cells in the brain. Cumulatively, these finding demonstrate for the first time that HNG may have the potential for attenuating Aβ-induced cognitive deficits by reducing inflammatory responses and apoptosis in vivo, which may add to the novel evidence for anti-inflammatory and antiapoptosis properties of HNG in AD treatment. [Copyright &y& Elsevier]

The amyloid β-protein precursor (AβPP) is best known as the parent molecule to the amyloid β-peptide that accumulates in the brains of patients with Alzheimer's disease. Secreted isoforms of AβPP that contain the Kunitz proteinase inhibitor domain are analogous to the previously identified cell-secreted proteinase inhibitor known as protease nexin-2 (PN2). Although PN2/AβPP is enriched in brain and in circulating blood platelets, little is understood of its physiological function and potential role in disease processes outside of amyloid β-peptide generation. We hypothesized that the potent inhibition of certain procoagulant proteinases by PN2/AβPP, coupled with its abundance in platelets and brain, indicate that it may function to regulate cerebral thrombosis. Here we show that specific and modest 2-fold overexpression of PN2/AβPP in circulating platelets of transgenic mice caused a marked inhibition of thrombosis in vivo. In contrast, deletion of PN2/AβPP in AβPP gene knockout mice resulted in a significant increase in thrombosis. Similarly, platelet PN2/AβPP transgenic mice developed larger hematomas in experimental intracerebral hemorrhage, whereas AβPP gene knockout mice exhibited reduced hemorrhage size. These findings indicate that PN2/AβPP plays a significant role in regulating cerebral thrombosis and that modest increases in this protein can profoundly enhance cerebral hemorrhage. [ABSTRACT FROM AUTHOR]