Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation

Obregon, Demian; Hou, Huayan; Deng, Juan; Giunta, Brian; Tian, Jun; Darlington, Donna; Shahaduzzaman,; Zhu, Yuyuan; Mori, Takashi; Mattson, Mark P.; Tan, Jun

doi:10.1038/ncomms1781

Cited by 146 publications

(137 citation statements)

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“…In addition, it has been shown that over-expression of human sAPPα ameliorates Aβ pathogenesis in APP/ PS1 mice. Correspondingly, immunoneutralization of sAPPα by antibody causes hippocampal neuronal apoptosis in this model (Obregon et al 2012). These evidences, taken together, highly suggest that elevated α-secretase levels in neuronal cell bodies, give them the ability to produces neuroprotective sAPPα and maximally reduce neurotoxic Aβ production, in turn protects hippocampal neurons in the relatively long-term survival in AD-like pathology.…”

Section: Discussionmentioning

confidence: 57%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

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Section: Discussionmentioning

confidence: 57%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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“…In the broader context of all these interactions and balance, TrkB FL beneficial effects can be associated even with over-all increased APP levels. Very recently it has been shown that sAPP-, the fragment generated by ADAMs from APP, can inhibit BACE1 activity [30] therefore TrkB FL could be involved in this mechanism by promoting sAPP- production and increasing BACE1 levels.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase receptor B isoforms alter APP and BACE1 endogenous levels independently of BDNF

Ansaloni¹,

Leung²,

Dubey³

et al. 2012

AAD

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Brain derived neurotrophic factor (BDNF) levels and signaling via the tyrosine receptor kinase B (TrkB) have been shown to be altered in Alzheimer's Disease. In addition, it has been reported that the isoforms of TrkB can differentially affect metabolism of amyloid precursor protein (APP). Conversely, A, a neurotoxic cleavage product of APP, has been shown to impair TrkB/ BDNF signaling. Therefore, we investigated whether the changes observed in APP metabolism were due to the isoform-specific effects of TrkB on either APP expression, and/or on the expression and activity of ADAM10 and BACE1. Since BDNF levels are decreased in AD, we focused on BDNF independent effects of the TrkB isoforms. We found that TrkB FL increases endogenous APP levels in both HEK293 and SH-SY5Y naïve cells. We did not find an increase in ADAM10 activity in HEK293 cells, but an increase in BA-CE1 levels. Additionally, we have found that TrkB FL is able to increase NFAT3 mediated transcriptional activity and we suggest that this causes transcriptional activation of the BACE1 promoter.

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Section: App Processingmentioning

confidence: 99%

“…As the α-site is within the Aβ cognate region, α-cleavage precludes Aβ formation. In addition, sAPPα itself can act as a BACE inhibitor [31,32] while αCTF is an inhibitor of γ-secretase [33]. Alternatively, in the anti-trophic pro-AD pathway, FL-APP can interact with BACE resulting in dimerization, endocytosis, and cleavage in the acidic endosomal compartment, generating sAPPβ and βCTF.…”

Section: Mutations In Adam10 and At Appα-and β-Cleavage Sites Alter Amentioning

confidence: 99%

“…Alternatively, in the trophic, anti-amyloidogenic anti-AD pathway, APP is cleaved by an α-secretase (putatively ADAM10) to generate the two fragments sAPPα and αCTF. These latter fragments [30] support synaptic maintenance and can inhibit the β pathway as cleavage at the α site precludes β cleavage and because sAPPα itself is a BACE inhibitor [31,32].The interaction of APP cleavage products with each other and non-APP-derived proteins is complex and the mechanisms by which these APP fragments exert their many effects is not fully elucidated [34]. It is known, however, that αCTF can inhibit γ-secretase activity [33] as it contains an intact γ-cleavage site.…”

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confidence: 99%

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2015

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Citation: Spilman P, Jagodzinska B, Bredesen DE, John V (2015) Enhancement of sAPPα as a Therapeutic Strategy for Alzheimer's and Other Neurodegenerative Diseases. J Alzheimers Neurodegener Dis 1: 001. Introduction Therapeutics for Alzheimer's Disease (AD)The number of cases of Alzheimer's Disease (AD) -the most prevalent age-associated dementia -is expected to increase rapidly as society ages, rising from approximately 5 million at present to 15 million cases by 2050 in the US [1], and currently there are no treatments that prevent onset or alter the course of the disease. AD is a progressive neurodegenerative disorder characterized by the presence of senile plaques, composed mainly of Amyloid β peptide (Aβ) [2,3], and the development of neurofibrillary tangles of hyper-phosphorylated tau (ptau) in brain tissue [4,5]. AD patients suffer from deficits in cognition, learning and memory, and exhibit impaired Long-Term Potentiation (LTP) [6] and a consistent deficit in cholinergic neurotransmission. The currently approved therapeutics include the acetylcholinesterase inhibitors donepezil, galantamine, rivastigmine, and tacrine which inhibit the breakdown of acetylcholine at the neuronal junction, and the N-Methyl-D-Aspartate (NMDA) receptor antagonist memantine, which reduces the excitotoxicity that results from NMDA receptor overstimulation in AD. Recently, the FDA has approved a fixed-dose combination of memantine hydrochloride extended release (Namenda XR) and donepezil hydrochloride (Namzaric) for moderate to severe AD-related dementia. These current therapeutics offer only temporary improvement in cognition and/or delay in progress of the disease, thus there is clearly a need for new approaches to and discovery of new targets for AD therapeutic development.More recent approaches to AD therapeutic development include re-purposing the anti-epileptic drug levetiracetam to address the seizure-like activity manifest in many AD patients [7,8], use of anti-diabetic drugs including intranasal insulin [9,10], and development of BACE inhibitors [11][12][13], including our own APP-selective BACE inhibitors [14], to name a few. It is hoped that some of these new approaches will provide benefit in AD, but it is very likely that truly effective treatment for AD will require multiple therapeutics working in concert -similar to the approach used for AIDS therapy -to address the many deficits in the disease. One component of this multi-modal therapy should restore and promote normal neuronal function, rather than just arrest a single deleterious process underlying the disease. It is our hypothesis and that of others that enhancement of trophic peptide sAPPα, or the activity of the enzyme ADAM10, could play this key role in therapy. Aβ plaques and the amyloid hypothesis in ADThe original evidence pointing to amyloid as causative in AD came from the finding of amyloid plaques in the brains of AD patients. It was ultimately determined that these plaques were comprised of Amyloid-β (Aβ) peptides [15,16] and based on the presenc...

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Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation

Cited by 146 publications

References 58 publications

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Tyrosine kinase receptor B isoforms alter APP and BACE1 endogenous levels independently of BDNF

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