Substrate-Specific Activation of α-Secretase by 7-Deoxy-Trans-Dihydronarciclasine Increases Non-Amyloidogenic Processing of β-Amyloid Protein Precursor

Accumulation of β-amyloid (Aβ) in the brain has been implicated in the pathology of Alzheimer’s disease (AD). Aβ is produced from the Aβ precursor protein (APP) through the amyloidogenic pathway by β-, and γ-secretase. Alternatively, APP can be cleaved by α-, and γ-secretase, precluding the production of Aβ. Thus, stimulating α-secretase mediated APP processing is considered a therapeutic option not only for decreasing Aβ production but for increasing neuroprotective sAPPα. We have previously reported that 7-deoxy-trans-dihydronarciclasine (E144), the active component of Lycoris chejuensis, decreases Aβ production by attenuating APP level, and retarding APP maturation. It can also improve cognitive function in the AD model mouse. In this study, we further analyzed the activating effect of E144 on α-secretase. Treatment of E144 increased sAPPα, but decreased β-secretase products from HeLa cells stably transfected with APP. E144 directly activated ADAM10 and ADAM17 in a substrate-specific manner both in cell-based and in cell-free assays. The Lineweaver–Burk plot analysis revealed that E144 enhanced the affinities of A Disintegrin and Metalloproteinases (ADAMs) towards the substrate. Consistent with this result, immunoprecipitation analysis showed that interactions of APP with ADAM10 and ADAM17 were increased by E144. Our results indicate that E144 might be a novel agent for AD treatment as a substrate-specific activator of α-secretase.

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Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease

Biological Chemistry ◽

10.1515/bc.2010.110 ◽

2010 ◽

Vol 391 (8) ◽

Cited By ~ 25

Author(s):

Vivian Hook ◽

Gregory Hook ◽

Mark Kindy

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Cathepsin B ◽

Memory Deficit ◽

Mutant Site ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Brain ◽

Aβ Production

Abstract Beta-amyloid (Aβ) in the brain is a major factor involved in Alzheimer's disease (AD) that results in severe memory deficit. Our recent studies demonstrate pharmacogenetic differences in the effects of inhibitors of cathepsin B to improve memory and reduce Aβ in different mouse models of AD. The inhibitors improve memory and reduce brain Aβ in mice expressing the wild-type (WT) β-secretase site of human APP, expressed in most AD patients. However, these inhibitors have no effect in mice expressing the rare Swedish (Swe) mutant amyloid precursor protein (APP). Knockout of the cathepsin B decreased brain Aβ in mice expressing WT APP, validating cathepsin B as the target. The specificity of cathepsin B to cleave the WT β-secretase site, but not the Swe mutant site, of APP for Aβ production explains the distinct inhibitor responses in the different AD mouse models. In contrast to cathepsin B, the BACE1 β-secretase prefers to cleave the Swe mutant site. Discussion of BACE1 data in the field indicate that they do not preclude cathepsin B as also being a β-secretase. Cathepsin B and BACE1 could participate jointly as β-secretases. Significantly, the majority of AD patients express WT APP and, therefore, inhibitors of cathepsin B represent candidate drugs for AD.

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Current theories for the molecular and cellular pathogenesis of Alzheimer's disease

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399401003167 ◽

2001 ◽

Vol 3 (16) ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Gunnar K. Gouras

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Process ◽

Amyloid Aβ ◽

Β Amyloid ◽

Cellular Pathogenesis ◽

Amyloid Cascade ◽

The Brain ◽

Aβ Production ◽

Prevailing View

Over the past decade, the prevailing view for the molecular and cellular pathogenesis of Alzheimer's disease (AD) has centred on the β-amyloid (Aβ) peptide that accumulates in vulnerable brain areas in the disease. The amyloid cascade hypothesis postulates that the build up of Aβ in the brain causes damage to neurons, leading to dysfunction and loss of neurons, and the clinical phenotype of the amnestic dementia characteristic of AD. All known mutations that result in autosomal dominant forms of early-onset familial AD cause increased production of Aβ42, a form of Aβ that is particularly relevant in AD. Other proteins that are crucial to the pathogenesis of AD are the presenilins 1 and 2, which are intimately involved with Aβ production and when mutated in familial forms of AD cause increases in Aβ42. Currently, challenges in AD research include determining the earliest pathological effects of Aβ42, how the important AD risk factor apolipoprotein E affects the disease process, whether presenilin is the elusive γ-secretase, and how levels of Aβ can be effectively reduced therapeutically.

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Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein endocytosis

10.1101/616540 ◽

2019 ◽

Author(s):

Tatiana Burrinha ◽

Ricardo Gomes ◽

Ana Paula Terrasso ◽

Cláudia Guimas Almeida

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Precursor Protein ◽

App Processing ◽

Early Endosomes ◽

Primary Mouse ◽

Β Amyloid ◽

Aβ Production

AbstractAging increases the risk of Alzheimer’s disease (AD). During normal aging synapses decline and β-Amyloid (Aβ) accumulates. An Aβ defective clearance with aging is postulated as responsible for Aβ accumulation, although a role for increased Aβ production with aging can also lead to Aβ accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous Aβ42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of Aβ production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases Aβ production, which contributes to aging-dependent decline in synapses.SummaryHow aging increases the risk of Alzheimer’s disease is not clear. We show that normal neuronal aging increases the intracellular production of β-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased Aβ production contributes to the aging-dependent synapse loss.

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Measurement of β-amyloid (Aβ) clearance from the brain using metabolic labeling to diagnose Alzheimer's disease (AD)

Science-Business eXchange ◽

10.1038/scibx.2011.22 ◽

2011 ◽

Vol 4 (1) ◽

pp. 22-22

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Metabolic Labeling ◽

Amyloid Aβ ◽

Β Amyloid ◽

Aβ Clearance ◽

The Brain

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The Effect of the APOE4 Gene on Accumulation of Aβ 40 After Brain Injury Cannot Be Reversed by Increasing apoE4 Protein

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlw049 ◽

2016 ◽

Vol 75 (8) ◽

pp. 770-778 ◽

Cited By ~ 5

Author(s):

Patricia M. Washington ◽

Mark P. Burns

Keyword(s):

Brain Injury ◽

Amyloid Precursor Protein Processing ◽

Biphasic Response ◽

Protein Levels ◽

Abnormal Accumulation ◽

Apoe Protein ◽

Rapid Clearance ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Brain

Abstract The apolipoprotein E (apoE) protein is involved in clearance of β-amyloid (Aβ) from the brain; and the APOE4 gene is associated with Aβ plaque formation in humans following traumatic brain injury (TBI). Here, we examined the association between apoE and Aβ 40 after experimental TBI and the effects of APOE alleles on this relationship. We report a biphasic response of soluble apoE protein after TBI with an acute reduction at 1 day postinjury followed by an increase at 7 days postinjury. TBI-induced Aβ 40 levels decreased as soluble apoE levels increased. In APOE4 mice there was a diminished apoE response to TBI that corresponded to prolonged accumulation of TBI-induced Aβ 40 versus that in APOE3 mice. Amyloid precursor protein processing was similar in APOE3 and APOE4 mice suggesting that impaired clearance was responsible for the abnormal accumulation of Aβ 40 in the latter. Treatment of APOE4 mice with bexarotene for 7 days increased apoE4 protein levels but was not sufficient to reduce TBI-induced Aβ 40 . Thus, rapid clearance of TBI-induced Aβ 40 occurs in mice but these pathways are impaired in APOE4 carriers. These data may help explain the deposition of Aβ in APOE4 carriers and the increased incidence of brain Aβ plaques following TBI.

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Editorial for the Genetics of Alzheimer’s Disease Special Issue: October 2021

Genes ◽

10.3390/genes12111794 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1794

Author(s):

Laura Ibanez ◽

Justin B. Miller

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gray Matter ◽

Neuronal Death ◽

Tau Proteins ◽

Special Issue ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Brain

Alzheimer’s disease is a complex and multifactorial condition regulated by both genetics and lifestyle, which ultimately results in the accumulation of β-amyloid (Aβ) and tau proteins in the brain, loss of gray matter, and neuronal death [...]

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Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Biomedicines ◽

10.3390/biomedicines8080272 ◽

2020 ◽

Vol 8 (8) ◽

pp. 272

Author(s):

Anaïs Bécot ◽

Charlotte Volgers ◽

Guillaume van Niel

Keyword(s):

Amyloid Precursor Protein ◽

Neurodegenerative Diseases ◽

Multivesicular Body ◽

Precursor Protein ◽

Aβ Peptides ◽

Amyloid Aβ ◽

Β Amyloid ◽

Novel Concept ◽

The Brain

In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

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Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs

International Journal of Molecular Sciences ◽

10.3390/ijms23010102 ◽

2021 ◽

Vol 23 (1) ◽

pp. 102

Author(s):

Giulia Sierri ◽

Roberta Dal Magro ◽

Barbara Vergani ◽

Biagio Eugenio Leone ◽

Beatrice Formicola ◽

...

Keyword(s):

Cholesterol Efflux ◽

Brain Parenchyma ◽

Reactive Astrocytes ◽

Cholesterol Transport ◽

Functional Changes ◽

Atp Binding Cassette Transporters ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Brain

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.

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The Choroid Plexus Removes β-Amyloid from Brain Cerebrospinal Fluid

Experimental Biology and Medicine ◽

10.1177/153537020523001011 ◽

2005 ◽

Vol 230 (10) ◽

pp. 771-776 ◽

Cited By ~ 80

Author(s):

Janelle S. Crossgrove ◽

G. Jane Li ◽

Wei Zheng

Keyword(s):

Cerebrospinal Fluid ◽

Choroid Plexus ◽

Volume Of Distribution ◽

Temperature Dependent ◽

Cellular Accumulation ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Brain ◽

And Diffusion ◽

Isolated Rat

β-Amyloid (Aβ) concentration in the cerebrospinal fluid (CSF) of the brain may be regulated by the choroid plexus, which forms a barrier between blood and brain CSF. Aβ uptake from CSF was determined as its volume of distribution (VD) into isolated rat choroid plexus tissue. The VD of [125l]Aβ1–40 was corrected by subtraction of the VD of [14C]sucrose, a marker for extracellular space and diffusion. Aβ uptake into choroid plexus was time and temperature dependent. Uptake of [125l]Aβ was saturable. Aβ uptake was not affected by addition of transthyretin or apolipoprotein E3. In studies with primary culture monolayers of choroidal epithelial cells in Transwells, Aβ permeability across cells, corrected by [14C]sucrose, was greater from the CSF-facing membrane than from the blood-facing membrane. Similarly, cellular accumulation of [125l]Aβ was concentrative from both directions and was greater from the CSF-facing membrane, suggesting a bias for efflux. Overall, these results suggest the choroid plexus selectively cleanses Aβ from the CSF by an undetermined mechanism(s), potentially reducing Aβ from normal brains and the brains of Alzheimer's disease patients.

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