scholarly journals Mitochondrial Membrane Potential Influences Aβ Production and Amyloid Precursor Protein localization

2021 ◽  
Author(s):  
Heather Wilkins ◽  
Benjamin Troutwine ◽  
Blaise Menta ◽  
Sharon Manley ◽  
Taylor Strope ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Mitochondrial Function ◽  
Protein Localization ◽  
Precursor Protein ◽  
Mitochondrial Activity ◽  
Mitochondrial Depolarization ◽  
Factors Associated ◽  
Amyloid Aβ ◽  
Fluid Biomarker ◽  
Aβ Production

Abstract Beta amyloid (Aβ), which derives from the amyloid precursor protein (APP), forms plaques and serves as a fluid biomarker in Alzheimer’s disease (AD). How Aβ forms from APP is known, but questions relating to APP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction and an Aβ/ APP/ mitochondria relationship exists. Here, we considered how mitochondrial biology may impact APP and Aβ biology. We showed that mitochondrial depolarization routes APP to, while hyperpolarization routes APP away from, the organelle. Mitochondrial APP and cell Aβ secretion inversely correlate, as cells with more mitochondrial APP secrete less Aβ, and cells with less mitochondrial APP secrete more Aβ. Overall, our findings indicate mitochondrial function alters APP localization and suggest enhanced mitochondrial activity or factors associated with enhanced mitochondrial activity promote Aβ secretion while depressed mitochondrial activity or factors associated with depressed mitochondrial activity minimize Aβ secretion. Our data complement other studies that indicate a mitochondrial, APP, and Aβ nexus, and could help explain why cerebrospinal fluid Aβ is lower in those with AD. Our data further suggest Aβ secretion could serve as a biomarker of cell or tissue mitochondrial function.

scholarly journals Copper inhibits β-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion

1999 ◽  
Vol 344 (2) ◽  
pp. 461-467 ◽  
Author(s):  
Thilo BORCHARDT ◽  
James CAMAKARIS ◽  
Roberto CAPPAI ◽  
Colin L. MASTERS ◽  
Konrad BEYREUTHER ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Protein Secretion ◽  
Chinese Hamster ◽  
Oxidative Modification ◽  
Precursor Protein ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Aβ Generation ◽  
Aβ Production ◽  
Stimulation Of

Previous studies have demonstrated that amyloid precursor protein (APP) can bind and reduce Cu(II) to Cu(I), leading to oxidative modification of APP. In the present study we show that adding copper to Chinese-hamster ovary (CHO) cells greatly reduced the levels of amyloid Aβ peptide (Aβ) both in parental CHO-K1 and in copper-resistant CHO-CUR3 cells, which have lower intracellular copper levels. Copper also caused an increase in the secretion of the APP ectodomain, indicating that the large decrease in Aβ release was not due to a general inhibition in protein secretion. There was an increase in intracellular full-length APP levels which paralleled the decrease in Aβ generation, suggesting the existence of two distinct regulating mechanisms, one acting on Aβ production and the other on APP synthesis. Maximal inhibition of Aβ production and stimulation of APP secretion was achieved in CHO-K1 cells at about 10 μM copper and in CHO-CUR3 cells at about 50 μM copper. This dose ‘window of opportunity’ at which copper promoted the non-amyloidogenic pathway of APP was confirmed by an increase in the non-amyloidogenic p3 fragment produced by α-secretase cleavage. Our findings suggest that copper or copper agonists might be useful tools to discover novel targets for anti-Alzheimer drugs and may prove beneficial for the prevention of Alzheimer's disease.

scholarly journals Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

2020 ◽  
Author(s):  
Hao Wang ◽  
Joshua A. Kulas ◽  
Heather A. Ferris ◽  
Scott B. Hansen
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Cholesterol Synthesis ◽  
Protein Localization ◽  
Super Resolution ◽  
Precursor Protein ◽  
Targeted Deletion ◽  
Amyloid Aβ

ABSTRACTAlzheimer’s Disease (AD) is characterized by the presence of β-Amyloid (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic marker for sporadic AD. In vitro evidence suggests apoE links to Aβ production through nanoscale lipid compartments (also called lipid rafts), but its regulation in vivo is unclear. Here we use super-resolution imaging in mouse brain to show apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) into lipid rafts where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid rafts where it interacts with α-secretase and gives rise to soluble APPα (sAPPα), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting the ratio of Aβ to sAPPα is regulated by the trafficking of the substrate, not the enzymes. Treatment of astrocytes with inflammatory cytokines IL-1β, IL-6 and TNF-α upregulates the synthesis of cholesterol in the astrocytes. We conclude that cholesterol is kept low in neurons to inhibit Aβ formation and enable astrocyte regulation of Aβ formation by cholesterol regulation.HighlightsApoE regulates amyloid precursor protein localization to rafts and its exposure to α-vs. β-secretase.α-, β-, and γ-Secretases are activated by substrate presentation.ApoE specifically transports astrocyte cholesterol to neurons.Astrocyte cholesterol synthesis disruption prevents Alzheimer’s-associated amyloid pathology in mice.

Mitochondrial Membrane Potential Influences Amyloid-β Protein Precursor Localization and Amyloid-β Secretion

2021 ◽  
pp. 1-14
Author(s):  
Heather M. Wilkins ◽  
Benjamin R. Troutwine ◽  
Blaise W. Menta ◽  
Sharon J. Manley ◽  
Taylor A. Strope ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Amyloid Β ◽  
Mitochondrial Activity ◽  
Amyloid Β Protein ◽  
Mitochondrial Depolarization ◽  
Protein Precursor ◽  
Β Protein ◽  
Bace1 Expression ◽  
Synthase Inhibitor ◽  
Fluid Biomarker

Background: Amyloid-β (Aβ), which derives from the amyloid-β protein precursor (AβPP), forms plaques and serves as a fluid biomarker in Alzheimer’s disease (AD). How Aβ forms from AβPP is known, but questions relating to AβPP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction, and an Aβ/AβPP mitochondria relationship exists. Objective: We considered how mitochondrial biology may impact AβPP and Aβ biology. Methods: SH-SY5Y cells were transfected AβPP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation Aβ levels were measured. β-secretase (BACE1) expression was measured. Mitochondrial localized full-length AβPP was also measured. All parameters listed were measured in ρ0 cells on an SH-SY5Y background. iPSC derived neurons were also used to verify key results. Results: We showed that mitochondrial depolarization routes AβPP to, while hyperpolarization routes AβPP away from, the organelle. Mitochondrial AβPP and cell Aβ secretion inversely correlate, as cells with more mitochondrial AβPP secrete less Aβ, and cells with less mitochondrial AβPP secrete more Aβ. An inverse relationship between secreted/extracellular Aβ and intracellular Aβ was observed. Conclusion: Our findings indicate mitochondrial function alters AβPP localization and suggest enhanced mitochondrial activity promote Aβ secretion while depressed mitochondrial activity minimize Aβ secretion. Our data complement other studies that indicate a mitochondrial, AβPP, and Aβ nexus, and could help explain why cerebrospinal fluid Aβ is lower in those with AD. Our data further suggest Aβ secretion could serve as a biomarker of cell or tissue mitochondrial function.

Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 1164-1173
Author(s):  
Siju Ellickal Narayanan ◽  
Nikhila Sekhar ◽  
Rajalakshmi Ganesan Rajamma ◽  
Akash Marathakam ◽  
Abdullah Al Mamun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Early Onset ◽  
Late Onset ◽  
Precursor Protein ◽  
Brain Disorder ◽  
Amyloid Aβ ◽  
T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

Understanding the structural requirements of cyclic sulfone hydroxyethylamines as hBACE1 inhibitors against Aβ plaques in Alzheimer's disease: a predictive QSAR approach

RSC Advances ◽  
2016 ◽  
Vol 6 (34) ◽  
pp. 28171-28186 ◽  
Author(s):  
Pravin Ambure ◽  
Kunal Roy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Structural Requirements ◽  
Amyloid Aβ

Beta (β)-site amyloid precursor protein cleaving enzyme 1 (BACE1) is one of the most important targets in Alzheimer's disease (AD), which is responsible for production and accumulation of beta amyloid (Aβ).

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

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.

Phosphatidylinositol‐4‐phosphate 5‐kinase type 1α attenuates Aβ production by promoting non‐amyloidogenic processing of amyloid precursor protein

2020 ◽  
Vol 34 (9) ◽  
pp. 12127-12146
Author(s):  
Po‐Fan Wu ◽  
Noopur Bhore ◽  
Yen‐Lurk Lee ◽  
Ju‐Yun Chou ◽  
Yun‐Wen Chen ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Amyloidogenic Processing ◽  
Phosphatidylinositol 4 ◽  
Aβ Production
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