scholarly journals Filling the void: a role for exercise-induced BDNF and brain amyloid precursor protein processing

2017 ◽  
Vol 313 (5) ◽  
pp. R585-R593 ◽  
Author(s):  
Rebecca E. K. MacPherson
Keyword(s):  
Insulin Resistance ◽  
Amyloid Precursor Protein ◽  
Significant Risk ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Amyloid Precursor Protein Processing ◽  
Direct Effects ◽  
App Processing ◽  
Β Amyloid ◽  
Exercise Induced

Inactivity, obesity, and insulin resistance are significant risk factors for the development of Alzheimer’s disease (AD). Several studies have demonstrated that diet-induced obesity, inactivity, and insulin resistance exacerbate the neuropathological hallmarks of AD. The aggregation of β-amyloid peptides is one of these hallmarks. β-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid precursor protein (APP) processing, leading to β-amyloid peptide formation. Understanding how BACE1 content and activity are regulated is essential for establishing therapies aimed at reducing and/or slowing the progression of AD. Exercise training has been proven to reduce the risk of AD as well as decrease β-amyloid production and BACE1 content and/or activity. However, these long-term interventions also result in improvements in adiposity, circulating metabolites, glucose tolerance, and insulin sensitivity making it difficult to determine the direct effects of exercise on brain APP processing. This review highlights this large void in our knowledge and discusses our current understanding of the direct of effect of exercise on β-amyloid production. We have concentrated on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the direct effects of exercise on reducing brain BACE1 content and activity as well as β-amyloid production. Future studies should aim to generate a greater understanding of how obesity and exercise can directly alter APP processing and AD-related pathologies. This knowledge could provide evidence-based hypotheses for designing therapies to reduce the risk of AD and dementia.

Cell line construction and maintenance for Lyso-IP and Endo-IP analysis of amyloid precursor protein processing v1

2021 ◽  
Author(s):  
Hankum Park ◽  
Frances V Hundley ◽  
Harper JW
Keyword(s):  
Amyloid Precursor Protein ◽  
Cell Line ◽  
Quantitative Proteomics ◽  
Protein Processing ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
App Processing ◽  
293 Cells ◽  
Line Construction ◽  
App Gene

Lyso-IP is a method that allows for the isolation of lysosomes for proteomics and metabolomics (dx.doi.org/10.17504/protocols.io.bybjpskn; dx.doi.org/10.17504/protocols.io.bx9hpr36). We have developed an analogous approach for purification of early/sorting endosomes (Endo-IP). In addition, we have found that endolysosomal purification via Lyso-IP and Endo-IP can be coupled with a quantitative proteomics workflow to obtain snapshots of Amyloid Precursor Protein (APP) processing to its Aβ products (Park et al. in submission). Here, we describe methods for cell line construction and maintenance of 293 cells with TMEM192-3xHA and 3xFLAG-EEA1, which are used for lysosome and endosome purification, respectively, with the addition of patient mutations to APP promotes processing. Cells with endogenously tagged TMEM192 and stably expressing FLAG-EEA1 are referred to as 293EL cells, for Endo-IP and Lyso-IP. These cells were also prepared in a form that has a deletion of the APP gene (293EL;APP-/-) and the same cells reconstituted with a lentivirus stably expressing APPSw;T700N to allow functional analysis of APP processing.

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.

The effect of neuronal activity on β-amyloid precursor protein (APP) processing in cultured cells

2017 ◽  
Vol 381 ◽  
pp. 664
Author(s):  
T. Ishiguro ◽  
K. Kasuga ◽  
K. Saito ◽  
N. Mezaki ◽  
T. Miura ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Neuronal Activity ◽  
Cultured Cells ◽  
Precursor Protein ◽  
App Processing ◽  
Β Amyloid

scholarly journals Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling

2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Claire S. Durrant ◽  
Karsten Ruscher ◽  
Olivia Sheppard ◽  
Michael P. Coleman ◽  
Ilknur Özen
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Vascular Pathology ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Beta Peptides ◽  
App Processing ◽  
Sprouting Angiogenesis ◽  
Organotypic Brain Slice ◽  
Bace1 Inhibition

AbstractAmyloid beta peptides (Aβ) proteins play a key role in vascular pathology in Alzheimer’s Disease (AD) including impairment of the blood–brain barrier and aberrant angiogenesis. Although previous work has demonstrated a pro-angiogenic role of Aβ, the exact mechanisms by which amyloid precursor protein (APP) processing and endothelial angiogenic signalling cascades interact in AD remain a largely unsolved problem. Here, we report that increased endothelial sprouting in human-APP transgenic mouse (TgCRND8) tissue is dependent on β-secretase (BACE1) processing of APP. Higher levels of Aβ processing in TgCRND8 tissue coincides with decreased NOTCH3/JAG1 signalling, overproduction of endothelial filopodia and increased numbers of vascular pericytes. Using a novel in vitro approach to study sprouting angiogenesis in TgCRND8 organotypic brain slice cultures (OBSCs), we find that BACE1 inhibition normalises excessive endothelial filopodia formation and restores NOTCH3 signalling. These data present the first evidence for the potential of BACE1 inhibition as an effective therapeutic target for aberrant angiogenesis in AD.

scholarly journals Generation of the β-Amyloid Peptide and the Amyloid Precursor Protein C-terminal Fragment γ Are Potentiated by FE65L1

2003 ◽  
Vol 278 (51) ◽  
pp. 51100-51107 ◽  
Author(s):  
Yang Chang ◽  
Giuseppina Tesco ◽  
William J. Jeong ◽  
Loren Lindsley ◽  
Elizabeth A. Eckman ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Protein C ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Terminal Fragment ◽  
Β Amyloid ◽  
Β Amyloid Peptide
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