Regulation of β cleavage of amyloid precursor protein

Wang, Junfeng; Ling, Rui; Wang, Yi-Zheng

doi:10.1007/s12264-010-0515-1

Cited by 9 publications

(4 citation statements)

References 84 publications

(77 reference statements)

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“…APP is synthesized in the endoplasmic reticulum and is found in the highest concentrations in neuron's trans-Golgi-network, suggesting that APP is associated with secretory pathways (Palacios et al, 1992;Stephens and Austen, 1996;Kitazume et al, 2001;Tam et al, 2014;Toh et al, 2017;Liu et al, 2019). There are two accepted proteolytic pathways for APP processing − non-amyloidogenic and amyloidogenic (Ishiura, 1991;Kojima and Omori, 1992;Sisodia, 1992;Roberts et al, 1994;Mills and Reiner, 1999;Soriano et al, 2001;Irizarry et al, 2004;Song et al, 2004;Chow et al, 2010;Wang et al, 2010;Tomita and Wong, 2011). The non-amyloidogenic pathway involves cleavage of APP by α-secretase at the plasma membrane, releasing soluble APPα (sAPPα) fragments into the extracellular environment, and normalizes AG genes and memory (Volmar et al, 2017).…”

Section: Lipids Contribute To Amyloid Precursor Protein Processingmentioning

confidence: 99%

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

2020

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Lipids constitute the bulk of the dry mass of the brain and have been associated with healthy function as well as the most common pathological conditions of the brain. Demographic factors, genetics, and lifestyles are the major factors that influence lipid metabolism and are also the key components of lipid disruption in Alzheimer's disease (AD). Additionally, the most common genetic risk factor of AD, APOE 4 genotype, is involved in lipid transport and metabolism. We propose that lipids are at the center of Alzheimer's disease pathology based on their involvement in the blood-brain barrier function, amyloid precursor protein (APP) processing, myelination, membrane remodeling, receptor signaling, inflammation, oxidation, and energy balance. Under healthy conditions, lipid homeostasis bestows a balanced cellular environment that enables the proper functioning of brain cells. However, under pathological conditions, dyshomeostasis of brain lipid composition can result in disturbed BBB, abnormal processing of APP, dysfunction in endocytosis/exocytosis/autophagocytosis, altered myelination, disturbed signaling, unbalanced energy metabolism, and enhanced inflammation. These lipid disturbances may contribute to abnormalities in brain function that are the hallmark of AD. The wide variance of lipid disturbances associated with brain function suggest that AD pathology may present as a complex interaction between several metabolic pathways that are augmented by risk factors such as age, genetics, and lifestyles. Herewith, we examine factors that influence brain lipid composition, review the association of lipids with all known facets of AD pathology, and offer pointers for potential therapies that target lipid pathways.

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Section: Lipids Contribute To Amyloid Precursor Protein Processingmentioning

confidence: 99%

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

2020

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“…The purpose of this review is to describe transcriptional regulations of BACE1. BACE1 regulation by translational modification, maturation and trafficking will not be treated as they have been nicely reviewed elsewhere [29,47-49]. …”

Section: The β-Secretase βApp-cleaving Enzymementioning

confidence: 99%

BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer’s disease

Chami

Checler

2012

Mol Neurodegeneration

135

103

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Alzheimer’s disease (AD) is a complex age-related pathology, the etiology of which has not been firmly delineated. Among various histological stigmata, AD-affected brains display several cellular dysfunctions reflecting enhanced oxidative stress, inflammation process and calcium homeostasis disturbance. Most of these alterations are directly or indirectly linked to amyloid β-peptides (Aβ), the production, molecular nature and biophysical properties of which likely conditions the degenerative process. It is particularly noticeable that, in a reverse control process, the above-described cellular dysfunctions alter Aβ peptides levels. β-secretase βAPP-cleaving enzyme 1 (BACE1) is a key molecular contributor of this cross-talk. This enzyme is responsible for the primary cleavage generating the N-terminus of “full length” Aβ peptides and is also transcriptionally induced by several cellular stresses. This review summarizes data linking brain insults to AD-like pathology and documents the key role of BACE1 at the cross-road of a vicious cycle contributing to Aβ production.

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“…The pathological hallmarks of AD are extracellular senile plaques (SPs) composed of amyloid β (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated microtubule-associated protein τ (2). Aβ aggregation and accumulation, derived from sequential cleavage of amyloid precursor protein (APP) mediated by β-and γ-secretases, is the triggering event in the process of AD (2)(3)(4). The Aβ oligomer is the main form which mediates the deleterious effect of Aβ as it fibrillates to form SPs.…”

Section: Introductionmentioning

confidence: 99%

microRNA-9 attenuates amyloidβ-induced synaptotoxicity by targeting calcium/calmodulin-dependent protein kinase kinase 2

Chang

Zhang

Wu-ping

et al. 2014

Molecular Medicine Reports

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The calcium/calmodulin-dependent protein kinase kinase 2, adenosine monophosphate-activated protein kinase (CAMKK2-AMPK) pathway mediated amyloid β42 (Aβ42)-induced synaptotoxicity and blockage of CAMKK2-protected neurons against the effect of Aβ42. Numerous microRNAs (miRNAs) were downregulated in response to Aβ42, including miR-9, a synapse-enriched miRNA that is decreased in Alzheimer's disease. In the present study the effect of miR-9 on Aβ42‑triggered CAMKK2-AMPK activation and the synaptotoxic impairment was investigated. Aβ42 oligomers were identified to be capable of inducing CAMKK2-AMPK pathway activation, which was attenuated by miR-9 overexpression. CAMKK2 was predicted to be a target of miR-9 using Pictar and Targetscan 6.2 Bioinformatics' algorithms. A luciferase activity assay and western blot analysis confirmed that miR-9 significantly inhibited CAMKK2 expression. Additionally, overexpression of miR-9 was sufficient to restore Aβ42-induced dendritic spine loss and rescued Aβ42-induced τ phosphorylation at Ser-262 mediated by the CAMKK2-AMPK pathway. The results of the present study demonstrated that miR-9 attenuated Aβ-induced synaptotoxicity by targeting CAMKK2.

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Regulation of β cleavage of amyloid precursor protein

Cited by 9 publications

References 84 publications

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer’s disease

microRNA-9 attenuates amyloidβ-induced synaptotoxicity by targeting calcium/calmodulin-dependent protein kinase kinase 2

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