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Franziska Rieche, Katia Carmine-Simmen, Burkhard Poeck, Doris Kretzschmar, Roland Strauss
The β-amyloid precursor protein (APP) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. APP is cleaved by various secretases whereby sequential processing by the β- and γ-secretases produces the β-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N-terminal sAPPβ fragments and the APP intracellular domain (AICD). Alternative cleavage by α-secretase results in slightly longer secreted sAPPα fragments and the identical AICD...
February 12, 2018: Current Biology: CB
Raphael Hesse, Björn von Einem, Franziska Wagner, Patricia Bott, Daniel Schwanzar, Rosemary J Jackson, Karl Josef Föhr, Ludwig Lausser, Katja S Kroker, Christian Proepper, Paul Walther, Hans A Kestler, Tara L Spires-Jones, Tobias Boeckers, Holger Rosenbrock, Christine A F von Arnim
One major pathophysiological hallmark of Alzheimer's disease (AD) is senile plaques composed of amyloid β (Aβ). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards Aβ production and soluble APPβ (sAPPβ) levels. Aβ is known to impair synaptic function; however, much less is known about the physiological functions of sAPPβ. The neurotrophic properties of sAPPα, derived from the non-amyloidogenic pathway of APP cleavage, are well-established, whereas only a few, conflicting studies on sAPPβ exist...
February 18, 2018: Experimental Neurology
Valerie T Y Tan, Bruce G Mockett, Shane M Ohline, Karen D Parfitt, Hollie E Wicky, Katie Peppercorn, Lucia Schoderboeck, Mohamad Fairuz Bin Yahaya, Warren P Tate, Stephanie M Hughes, Wickliffe C Abraham
Alzheimer's disease (AD) is a neurodegenerative disease driven in large part by accumulated deposits in the brain of the amyloid precursor protein (APP) cleavage product amyloid-β peptide (Aβ). However, AD is also characterised by reductions in secreted amyloid precursor protein-alpha (sAPPα), an alternative cleavage product of APP. In contrast to the neurotoxicity of accumulated Αβ, sAPPα has many neuroprotective and neurotrophic properties. Increasing sAPPα levels has the potential to serve as a therapeutic treatment that mitigates the effects of Aβ and rescue cognitive function...
February 9, 2018: Molecular Brain
Brent D Aulston, Jason Shapansky, YaWen Huang, Gary L Odero, Gordon W Glazner
Secreted amyloid precursor protein alpha (sAPPα) is a potent neurotrophin in the CNS but a dedicated receptor has not been found. However, protein interactions involving amyloid beta (Aβ), a peptide cleaved from the same parent peptide as sAPPα, indicate that insulin receptors (IRs) could be a target of amyloid peptides. In this study, in vitro analysis of cortical neuronal cultures revealed that exogenous sAPPα increased IR phosphorylation in the absence of insulin. Furthermore, in an APP overexpressing mouse model, sAPPα bound IRs in the cortex with significantly greater binding in hypoinsulinemic animals...
February 2, 2018: Experimental Neurology
Raquel Coronel, Adela Bernabeu-Zornoza, Charlotte Palmer, Mar Muñiz-Moreno, Alberto Zambrano, Eva Cano, Isabel Liste
Amyloid precursor protein (APP) is a member of the APP family of proteins, and different enzymatic processing leads to the production of several derivatives that are shown to have distinct biological functions. APP is involved in the pathology of Alzheimer's disease (AD), the most common neurodegenerative disorder causing dementia. Furthermore, it is believed that individuals with Down syndrome (DS) have increased APP expression, due to an extra copy of chromosome 21 (Hsa21), that contains the gene for APP...
January 30, 2018: Molecular Neurobiology
Rafaela Peron, Izabela Pereira Vatanabe, Patricia Regina Manzine, Antoni Camins, Márcia Regina Cominetti
ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer's disease (AD)...
January 29, 2018: Pharmaceuticals
Ruohan Sun, Tongrong He, Yujun Pan, Zvonimir S Katusic
The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in APP expression thereby resulting in reduced secretion of soluble APPα (sAPPα). In contrast, β-site APP cleaving enzyme (BACE1) expression and production of amyloid β (Aβ)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with BACE1 inhibitor IV inhibited Aβ generation and increased sAPPα production by enhancing a disintegrin and metalloprotease (ADAM)10 expression...
January 15, 2018: Aging
Benedikt Beckert, Amparo Acker-Palmer, Walter Volknandt
Employing hippocampal synaptosomes from APP-deleted mice we analyzed immediate effects of Aβ42 peptide in its oligomeric or fibrillar assembly or of sAPPα protein on their bioenergetic activity. Upon administration of oligomeric Aβ42 peptide for 30 min we observed a robust decrease both in mitochondrial activity and in mitochondrial membrane potential. In contrast the respective fibrillary or scrambled peptides showed no effect, indicating that inhibition strictly depends on the oligomerization status of the peptide...
June 27, 2017: Biological Chemistry
Tongrong He, Ruohan Sun, Anantha Vr Santhanam, Livius V d'Uscio, Tong Lu, Zvonimir S Katusic
The mechanisms underlying dysfunction of cerebral microvasculature induced by type 1 diabetes (T1D) are not fully understood. We hypothesized that in cerebral microvascular endothelium, α-processing of amyloid precursor protein (APP) is impaired by T1D. In cerebral microvessels derived from streptozotocin (STZ)-induced T1D mice protein levels of APP and its α-processing enzyme, a disintegrin and metalloprotease 10 (ADAM10) were significantly decreased, along with down-regulation of adenylate cyclase 3 (AC3) and enhanced production of thromboxane A2 (TXA2)...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
Xi Kuang, Hong-Jing Zhou, Amy H Thorne, Xi-Nan Chen, Lin-Jiao Li, Jun-Rong Du
Emerging evidence suggests that alpha-processing single transmembrane proteins, amyloid precursor protein (APP) and anti-aging protein Klotho, are likely to be involved in the progression of Alzheimer's disease (AD). The natural phthalide Ligustilide (LIG) has been demonstrated to protect against aging- and amyloid-β (Aβ)-induced brain dysfunction in animal models. The present study is to investigate the effects of LIG on cognitive deficits and metabolism of both APP and Klotho and its underlying mechanism in AD double-transgenic (APP/PS1) mice and cultured human cells...
2017: Frontiers in Aging Neuroscience
Teneka Jean-Louis, Patricia Rockwell, Maria E Figueiredo-Pereira
Regulation of the amyloid precursor protein (APP) processing by α- and β-secretases is of special interest to Alzheimer's disease (AD), as these proteases prevent or mediate amyloid beta formation, respectively. Neuroinflammation is also implicated in AD. Our data demonstrate that the endogenous mediator of inflammation prostaglandin J2 (PGJ2) promotes full-length APP (FL-APP) processing by α- and β-secretases. The decrease in FL-APP was independent of proteasomal, lysosomal, calpain, caspase, and γ-secretase activities...
November 14, 2017: Neurobiology of Aging
Claude-Henry Volmar, Hasib Salah-Uddin, Karolina J Janczura, Paul Halley, Guerline Lambert, Andrew Wodrich, Sivan Manoah, Nidhi H Patel, Gregory C Sartor, Neil Mehta, Nancy T H Miles, Sachi Desse, David Dorcius, Michael D Cameron, Shaun P Brothers, Claes Wahlestedt
Alzheimer's disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single drug would simultaneously affect the expression of a number of defined AD-related targets. We show that the small-molecule histone deacetylase inhibitor M344 reduces beta-amyloid (Aβ), reduces tau Ser396 phosphorylation, and decreases both β-secretase (BACE) and APOEε4 gene expression...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
Sérgio Monteiro de Almeida, Clea E Ribeiro, Indianara Rotta, Mauro Piovesan, Bin Tang, Florin Vaida, Sonia Mara Raboni, Scott Letendre, Michael Potter, Meire S Batistela Fernandes, Ronald J Ellis
Based on prior reports that the HIV-1 Tat protein modulates amyloid-beta (Aβ) metabolism, this study aimed to compare CSF neural injury biomarkers between 27 patients with HIV subtype B, 26 patients with HIV subtype C, 18 healthy HIV-negative controls, and 24 patients with Alzheimer's disease (AD). Immunoassays were used to measure soluble amyloid precursor protein α and β (sAPPα, sAPPβ), Aβ oligomers 38, 40, 42, and Aβ-total; phosphorylated tau (P-tau181 ), and total tau (T-tau). Comparisons between HIV(+) and HIV(-) (including AD) were adjusted by linear regression for gender and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression...
February 2018: Journal of Neurovirology
Christiane Rose, Emilie Dorard, Mickael Audrain, Lucie Gorisse-Hussonnois, Nathalie Cartier, Jérome Braudeau, Bernadette Allinquant
Amyloid precursor protein (APP), a key molecule of Alzheimer disease, is metabolized in 2 antagonist pathways generating the soluble APP alpha (sAPPα) having neuroprotective properties and the beta amyloid (Aβ) peptide at the origin of neurotoxic oligomers, particularly Aβ1-42. Whether extracellular Aβ1-42 oligomers modulate the formation and secretion of sAPPα is not known. We report here that the addition of Aβ1-42 oligomers to primary cortical neurons induced a transient increase in α-secretase activity and secreted sAPPα 6-9 hours later...
January 2018: Neurobiology of Aging
Wataru Araki, Kotaro Hattori, Kazutomi Kanemaru, Yuma Yokoi, Yoshie Omachi, Harumasa Takano, Masuhiro Sakata, Sumiko Yoshida, Tadashi Tsukamoto, Miho Murata, Yuko Saito, Hiroshi Kunugi, Yu-Ichi Goto, Utako Nagaoka, Masahiro Nagao, Takashi Komori, Kunimasa Arima, Kenji Ishii, Shigeo Murayama, Hiroshi Matsuda, Hisateru Tachimori, Yumiko M Araki, Hidehiro Mizusawa
BACKGROUND: Because soluble (or secreted) amyloid precursor protein-β (sAPPβ) and -α (sAPPα) possibly reflect pathological features of Alzheimer's disease (AD), they are potential biomarker candidates for dementia disorders, including AD and mild cognitive impairment (MCI) due to AD (MCI-AD). However, controversial results have been reported regarding their alterations in the cerebrospinal fluid (CSF) of AD and MCI-AD patients. In this study, we re-assessed the utility of sAPPα and sAPPβ in CSF as diagnostic biomarkers of dementia disorders...
2017: Biomarker Research
Emilie Dorard, Stéphanie Chasseigneaux, Lucie Gorisse-Hussonnois, Cédric Broussard, Thierry Pillot, Bernadette Allinquant
Amyloid precursor protein (APP) is cleaved not only to generate the amyloid peptide (Aß), involved in neurodegenerative processes, but can also be metabolized by alpha secretase to produce and release soluble N-terminal APP (sAPPα), which has many properties including the induction of axonal elongation and neuroprotection. The mechanisms underlying the properties of sAPPα are not known. Here, we used proteomic analysis of mouse cortico-hippocampal membranes to identify the neuronal specific alpha3 (α3)-subunit of the plasma membrane enzyme Na, K-ATPase (NKA) as a new binding partner of sAPPα...
October 5, 2017: Molecular Neurobiology
Wanyue Huang, Ping Cheng, Kaiyuan Yu, Yanfei Han, Miao Song, Yanfei Li
Aluminum (Al) is a neurotoxicant and cause β-amyloid (Aβ) peptides aggregation and tau hyperphosphorylation. Hyperforin (HF) is one of the major active constituents of the extracts of St. John's Wort (Hypericum perforatum), can treat Alzheimer's disease (AD) and other diseases involving peptide accumulation and cognition impairment. To determine the effects of HF on Al-induced Aβ formation and tau hyperphosphorylation, PC12 cells were cultured and treated with Al-malt (500μM) and/or HF (1μM). The results showed that HF treatment significantly attenuated Al-malt-induced Aβ1-42 production by reducing the expressions of APP, BACE1 and PS1, while increasing the expressions of sAPPα, ADAM9/10/17, and tau phosphorylation in PC12 cells...
September 26, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Gemma Llufriu-Dabén, Alex Carrete, Elena Chierto, Jo Mailleux, Emeline Camand, Anne Simon, Tim Vanmierlo, Christiane Rose, Bernadette Allinquant, Jerome J A Hendriks, Charbel Massaad, Delphine Meffre, Mehrnaz Jafarian-Tehrani
Remyelination is an endogenous regenerative process of myelin repair in the central nervous system (CNS) with limited efficacy in demyelinating disorders. As strategies enhancing endogenous remyelination become a therapeutic challenge, we have focused our study on α-secretase-induced sAPPα release, a soluble endogenous protein with neuroprotective and neurotrophic properties. However, the role of sAPPα in remyelination is not known. Therefore, we investigated the remyelination potential of α-secretase-induced sAPPα release following CNS demyelination in mice...
September 18, 2017: Neurobiology of Disease
M Isabel G Lopez Sanchez, Hayley S Waugh, Andrew Tsatsanis, Bruce X Wong, Jonathan G Crowston, James A Duce, Ian A Trounce
Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPα) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer's disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Aβ) at the expense of sAPPα and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Aβ and mitochondrial function is unclear...
August 29, 2017: Scientific Reports
Yu-Ting Chen, Wu-Yan Chen, Xiao-Tian Huang, Ye-Chun Xu, Hai-Yan Zhang
Amyloid precursor protein (APP) and iron both play pivotal roles in the central nervous system, but whether and how iron influences the processing of endogenous APP in neurons remain unclear. Here, we investigated the regulatory effects and underlying mechanisms of iron on non-amyloidogenic and amyloidogenic processing of APP in rat primary cortical neurons. Treatment of the neurons with ferric ammonium citrate (FAC, 100 μmol/L) markedly facilitated the non-amyloidogenic processing of APP, as evidenced by a robust increase in α-secretase-derived carboxy-terminal fragment α (CTFα)...
August 24, 2017: Acta Pharmacologica Sinica
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