Neuropeptide Changes in Cortical and Deep Gray Structures in Alzheimer's Disease

Roeske, L; Auchus, Alexander P.

doi:10.1515/revneuro.1995.6.4.317

Cited by 5 publications

(4 citation statements)

References 127 publications

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“…Interactions of KPI/APP and PTP in vivo are supported by findings that they are normal components of neurosecretory vesicles. Under abnormal conditions, detection of changes in levels of expression of KPI/APP and certain neuropeptides in Alzheimer's disease (68,69) suggest that the role of KPI/APP in proneuropeptide processing should be investigated in disease conditions. It will be important in future studies to elucidate how KPI/APP and PTP interactions may modify physiological production of active enkephalins and neuropeptides that mediate neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

The Kunitz Protease Inhibitor Form of the Amyloid Precursor Protein (KPI/APP) Inhibits the Proneuropeptide Processing Enzyme Prohormone Thiol Protease (PTP)

Hook¹,

Sei²,

Yasothornsrikul³

et al. 1999

Journal of Biological Chemistry

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Proteolytic processing of proenkephalin and proneuropeptides is required for the production of active neurotransmitters and peptide hormones. Variations in the extent of proenkephalin processing in vivo suggest involvement of endogenous protease inhibitors. This study demonstrates that "protease nexin 2 (PN2)," the secreted form of the kunitz protease inhibitor (KPI) of the amyloid precursor protein (APP), potently inhibited the proenkephalin processing enzyme known as prohormone thiol protease (PTP), with a K i,app of 400 nM. Moreover, PTP and PN2 formed SDS-stable complexes that are typical of kunitz protease inhibitor interactions with target proteases. In vivo, KPI/APP (120 kDa), as well as a truncated form of KPI/APP that resembles PN2 in apparent molecular mass (110 kDa), were colocalized with PTP and (Met)enkephalin in secretory vesicles of adrenal medulla (chromaffin granules). KPI/APP (110 -120 kDa) was also detected in pituitary secretory vesicles that contain PTP. In chromaffin cells, calcium-dependent secretion of KPI/APP with PTP and (Met)enkephalin demonstrated the colocalization of these components in functional secretory vesicles. These results suggest a role for KPI/APP inhibition of PTP in regulated secretory vesicles. In addition, these results are the first to identify an endogenous protease target of KPI/APP, which is developmentally regulated in aging and Alzheimer's disease.Peptide neurotransmitters and hormones are synthesized as protein precursors that require proteolytic processing to generate active neuropeptides. Proneuropeptide precursors are routed from the rough endoplasmic reticulum to Golgi apparatus and secretory vesicles (1, 2). The presence of proneuropeptides and processed peptide products within secretory vesicles indicates that corresponding proteases for proneuropeptide processing are largely present within such vesicles. Secretory vesicles of adrenal medulla, known as chromaffin granules, have been widely used as a model system for studying neuropeptide biosynthetic enzymes (2-4). These vesicles contain several neuropeptides, including high levels of enkephalin opioid peptides (5-7) and neuropeptide Y (8), as well as galanin (9), somatostatin (7), and others.In our studies of proneuropeptide processing enzymes in chromaffin granules, the major proenkephalin processing enzyme was identified as a novel cysteine protease known as prohormone thiol protease (PTP) 1 (2, 10 -14). PTP cleaves proenkephalin at dibasic and monobasic basic residues (Arg and Lys) to generate enkephalin-related peptides that are present in adrenal medulla in vivo (12,13,15,16). Proenkephalin processing in chromaffin granules is also mediated, to a lesser degree, by the subtilisin-like prohormone convertase 1 (PC1) and PC2 enzymes (17) and by a 70-kDa aspartyl protease resembling the pituitary proopiomelanocortin-converting enzyme (18).It is known that the extent of proenkephalin processing in adrenal medulla, in vivo, is limited, because only 10% of (Met)-enkephalin exists as completely processed pent...

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Section: Discussionmentioning

confidence: 99%

The Kunitz Protease Inhibitor Form of the Amyloid Precursor Protein (KPI/APP) Inhibits the Proneuropeptide Processing Enzyme Prohormone Thiol Protease (PTP)

Hook¹,

Sei²,

Yasothornsrikul³

et al. 1999

Journal of Biological Chemistry

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“…Neuropeptides, essential signaling molecules originating from neurons or endocrine cells, serve as a resource for obtaining dynamic information on neuronal processes. 1 To date, neuropeptides have provided valuable insight into biological disorders including Alzheimer's disease 2,3 and obesity. 4−6 Mass spectrometry (MS) is revered for its high accuracy and sensitivity and has been utilized in many neuropeptide studies to date.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Neuropeptides, essential signaling molecules originating from neurons or endocrine cells, serve as a resource for obtaining dynamic information on neuronal processes . To date, neuropeptides have provided valuable insight into biological disorders including Alzheimer’s disease , and obesity. − Mass spectrometry (MS) is revered for its high accuracy and sensitivity and has been utilized in many neuropeptide studies to date. − With regard to processing MS data and subsequently obtaining peptide–spectrum matches (PSMs), database searching is a routine method, which compares the theoretical spectrum of a peptide with an experimental spectrum to make identifications. The area of database searching has seen tremendous growth in recent decades, with many software packages available for use including MSFragger, MaxQuant, PEAKS, Comet, and MetaMorpheus, each of which were designed for application in proteomics investigations.…”

Section: Introductionmentioning

confidence: 99%

EndoGenius: Optimized Neuropeptide Identification from Mass Spectrometry Datasets

Fields,

Vu,

Dang

et al. 2024

J. Proteome Res.

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Neuropeptides represent a unique class of signaling molecules that have garnered much attention but require special consideration when identifications are gleaned from mass spectra. With highly variable sequence lengths, neuropeptides must be analyzed in their endogenous state. Further, neuropeptides share great homology within families, differing by as little as a single amino acid residue, complicating even routine analyses and necessitating optimized computational strategies for confident and accurate identifications. We present EndoGenius, a database searching strategy designed specifically for elucidating neuropeptide identifications from mass spectra by leveraging optimized peptide–spectrum matching approaches, an expansive motif database, and a novel scoring algorithm to achieve broader representation of the neuropeptidome and minimize reidentification. This work describes an algorithm capable of reporting more neuropeptide identifications at 1% false-discovery rate than alternative software in five Callinectes sapidus neuronal tissue types.

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“…The neuropeptides are a diverse class of molecules in the brain that are involved in numerous physical functions. The rationale underlying this new therapeutic strategy derives from the fact that neuropeptides are naturally produced in the brain (and are therefore not likely to be neurotoxic), whereas extensive clinical studies show that patients with AD have low levels of neuropeptides in the brain (and thus neuropeptides are likely to be neuroprotective). − Specifically, the low levels have been recognized in parts of the brain that implicated in learning and memory: cortex and hippocampus . Moreover, it has been reviewed that neuropeptides may be potential drug targets for different treatments for the nervous-system disroders and have neuroprtective effects as anti-Aβ toxicity …”

Section: Introductionmentioning

confidence: 99%

Assessments of the Effect of Neurokinin B on Toxic Aβ Aggregates in Alzheimer’s Disease with the Molecular Mechanisms’ Action

Press-Sandler

Miller

2020

ACS Chem. Neurosci.

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Clinical trials of past and current treatments for Alzheimer's disease (AD) patients on the market suffer from the dual drawbacks of a lack of efficacy and side effects. Neuropeptides have been highlighted by their potential to protect cells against AD and can reverse the toxic effect induced by Aβ in cultured neurons. One of the neuropeptides that has insufficient attention in the literature as a potential treatment for prevention of the progression of AD is neurokinin B (NKB). There are critical and unresolved questions concerning the activation, and the molecular mechanisms underlying NKB effect on prevention of Aβ aggregation remain unknown. The current work identifies for the first time the specific interactions that contribute to the inhibition and prevention of initial seeding of polymorphic earlystage dimers. Three main conclusions are observed in this work. First, NKB inhibits formation of polymorphic early-stage fibrillar Aβ dimers. The efficiency of the inhibition depends on the concentration of NKB (i.e., NKB:Aβ ratio). Second, NKB has an excellent effect of preventing the formation of initial seeding of early-stage nonfibrillar Aβ dimers. Third, NKB peptides may self-assemble to form cross-α fibril-like structure during the inhibition activity of the polymorphic early-stage fibrillar Aβ dimers but not during the prevention activity of early-stage nonfibrillar Aβ dimers. The work provides crucial information for future experimental studies to approve the functional effect of NKB on inhibition and prevention of Aβ polymorphic early-stage oligomers.

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Neuropeptide Changes in Cortical and Deep Gray Structures in Alzheimer's Disease

Cited by 5 publications

References 127 publications

The Kunitz Protease Inhibitor Form of the Amyloid Precursor Protein (KPI/APP) Inhibits the Proneuropeptide Processing Enzyme Prohormone Thiol Protease (PTP)

The Kunitz Protease Inhibitor Form of the Amyloid Precursor Protein (KPI/APP) Inhibits the Proneuropeptide Processing Enzyme Prohormone Thiol Protease (PTP)

EndoGenius: Optimized Neuropeptide Identification from Mass Spectrometry Datasets

Assessments of the Effect of Neurokinin B on Toxic Aβ Aggregates in Alzheimer’s Disease with the Molecular Mechanisms’ Action

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