Amyloidogenic Processing of Amyloid Precursor Protein: Evidence of a Pivotal Role of Glutaminyl Cyclase in Generation of Pyroglutamate-Modified Amyloid-β†

The role of HS (heparan sulphate) in the pathology of AD (Alzheimer's disease) is multifaceted. HS and other glycosaminoglycans have been widely reported to be associated with neuritic plaques. HS has also been shown to promote the aggregation of Aβ (amyloid β-peptide), the proteinaceous component of neuritic plaques. Recently, we described a novel and contrasting role for HS in the pathology of AD: HS can inhibit the formation of Aβ, by directly interacting with the protease BACE1 (β-site amyloid precursor protein cleaving enzyme 1; β-secretase 1), that cleaves the amyloid precursor protein and is the rate limiting step in the generation of Aβ. Here, we review the current roles of HS and the potential for HS-derivatives in the treatment of AD.

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Abstract TP486: Role of Beta-Site Amyloid Precursor Protein-Cleaving Enzyme 2 in the Metabolism of Amyloid Precursor Protein in Human Brain Microvascular Endothelial Cells

Stroke ◽

10.1161/str.51.suppl_1.tp486 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Tongrong He ◽

Zvonimir S Katusic

Keyword(s):

Protein Expression ◽

Amyloid Precursor Protein ◽

Precursor Protein ◽

Protective Function ◽

Protein Levels ◽

Genetic Inactivation ◽

Amyloidogenic Processing ◽

Protein Expressions ◽

App Metabolism

Under physiological conditions, β-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) cleaves APP within Aβ sequence thereby functioning like a α-secretase. However, BACE2 could also function as a conditional β-secretase during aging, contributing to Alzheimer’s disease pathogenesis. To date the physiological functions of BACE2 in endothelium are largely unknown. The present study is therefore designed to investigate the role of BACE2 in APP metabolism in human BMECs. Cultured human BMECs (passage 5-6 or passage 22) were treated with BACE2siRNA (30 nM, for 3 days), levels of soluble APPα (sAPPα, a neurotrophic product of non-amyloidogenic processing of APP) and Aβ40 in the supernatant were measured. In human BMECs (passage 5-6), genetic inactivation of BACE2 significantly decreased production of sAPPα (n=12, P<0.05), but had no effect on production of Aβ40 (n=9, P>0.05). BACE2siRNA treatment significantly suppressed APP protein expression (n=7, P<0.05), but augmented protein levels of BACE1 (n=7, P<0.05). Genetic inactivation of BACE2 did not change protein levels of mature ADAM10 (n=7, P>0.05). Thus, reduced sAPPα secretion by BACE2siRNA treatment is likely caused not only by decreased α-secretase-like function of BACE2, but also by reduced APP expression. We further examined the effects of BACE2siRNA in senescent human BMECs. In cultured human BMECs (passage 22), protein expressions of senescent markers (p 21Cip1 and p 16INK4a ) were significantly increased (n=4, P<0.05). Genetic inactivation of BACE2 in senescent human BMECs also significantly suppressed secretion of sAPPα (n=8, P<0.05), but did not affect Aβ40 production (n=8, P>0.05). BACE2-siRNA treatment significantly inhibited protein expressions of APP and mature ADAM10 (n=7, P<0.05), but did not change BACE1 protein expression (n=7, P>0.05). Thus in senescent human BMECs, reduced APP expression and impaired α-processing may play important roles in the decreased sAPPα production. Since our previous studies have demonstrated that endothelial production of sAPPα significantly contributes to the sAPPα content in the hippocampus, our current findings suggests that inhibition of BACE2 could impair protective function of sAPPα in the hippocampus.

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Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Journal of Biological Chemistry ◽

10.1074/jbc.m807345200 ◽

2009 ◽

Vol 284 (18) ◽

pp. 11863-11872 ◽

Cited By ~ 57

Author(s):

Madepalli K. Lakshmana ◽

Il-Sang Yoon ◽

Eunice Chen ◽

Elizabetta Bianchi ◽

Edward H. Koo ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Amyloid Β ◽

Precursor Protein ◽

Amyloid Β Peptide

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Role of Amyloid Precursor Protein, Amyloid-β and γ-Secretase in Cholesterol Maintenance

Neurodegenerative Diseases ◽

10.1159/000095271 ◽

2006 ◽

Vol 3 (4-5) ◽

pp. 305-311 ◽

Cited By ~ 12

Author(s):

Tobias Hartmann

Keyword(s):

Amyloid Precursor Protein ◽

Amyloid Β ◽

Precursor Protein

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The C99 domain of the amyloid precursor protein is a disordered membrane phase-preferring protein

10.1101/2020.11.25.397893 ◽

2020 ◽

Author(s):

Ricardo Capone ◽

Ajit Tiwari ◽

Arina Hadziselimovic ◽

Yelena Peskova ◽

James M. Hutchison ◽

...

Keyword(s):

Plasma Membrane ◽

Amyloid Precursor Protein ◽

Protein Interactions ◽

Strong Association ◽

Amyloid Β ◽

Membrane Vesicles ◽

Precursor Protein ◽

Plasma Membrane Vesicles ◽

Amyloidogenic Processing ◽

Raft Domains

AbstractProcessing of the amyloid precursor protein (APP) via the amyloidogenic pathway is associated with the etiology of Alzheimer’s disease. The cleavage of APP by β-secretase to generate the transmembrane 99-residue C-terminal fragment (C99) and subsequent processing of C99 by γ-secretase to yield amyloid-β (Aβ) peptides are essential steps in this pathway. Biochemical evidence suggests amyloidogenic processing of C99 occurs in cholesterol- and sphingolipid-enriched liquid ordered phase membrane raft domains. However, direct evidence that C99 preferentially associates with rafts has remained elusive. Here, we test this idea by quantifying the affinity of C99-GFP for raft domains in cell-derived giant plasma membrane vesicles. We find that C99 is essentially excluded from ordered domains in HeLa cells, SH-SY5Y cells and neurons, instead exhibiting a strong (roughly 90%) affinity for disordered domains. The strong association of C99 with disordered domains occurs independently of its cholesterol binding activity, homodimerization, or the familial Alzheimer disease Arctic mutation. Finally, we confirm previous studies suggesting that C99 is processed in the plasma membrane by α-secretase, in addition to the well-known γ-secretase. These findings suggest that C99 itself lacks an intrinsic affinity for raft domains, implying either that amyloidogenic processing of the protein occurs in disordered regions of the membrane, that processing involves a marginal sub-population of C99 found in rafts, or that as-yet-unidentified protein-protein interactions involving C99 in living cells drive it into rafts to promote its cleavage therein.

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Inhibition of Wnt signaling induces amyloidogenic processing of amyloid precursor protein and the production and aggregation of Amyloid-β (Aβ)42peptides

Journal of Neurochemistry ◽

10.1111/jnc.13873 ◽

2016 ◽

Vol 139 (6) ◽

pp. 1175-1191 ◽

Cited By ~ 29

Author(s):

Cheril Tapia-Rojas ◽

Patricia V. Burgos ◽

Nibaldo C. Inestrosa

Keyword(s):

Amyloid Precursor Protein ◽

Wnt Signaling ◽

Amyloid Β ◽

Precursor Protein ◽

Amyloidogenic Processing

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

Current Protein and Peptide Science ◽

10.2174/1389203721666200921152246 ◽

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.

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