Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity

Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Schilling, Sandra [verfasserIn] Pradhan, Ajay Heesch, Amelie Helbig, Andrea Blennow, Kaj Koch, Christian Bertgen, Lea Koo, Edward H. Brinkmalm, Gunnar Zetterberg, Henrik Kins, Stefan Eggert, Simone

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Alzheimer’s disease Amyloid precursor protein Familial Alzheimer disease Beta Amyloid Trafficking Processing

Anmerkung:	© The Author(s) 2023

Übergeordnetes Werk:	Enthalten in: Acta Neuropathologica Communications - London : Biomed Central, 2013, 11(2023), 1 vom: 01. Juni
Übergeordnetes Werk:	volume:11 ; year:2023 ; number:1 ; day:01 ; month:06

Links:	Volltext

DOI / URN:	10.1186/s40478-023-01577-y

Katalog-ID:	SPR051739666

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allfields	10.1186/s40478-023-01577-y doi (DE-627)SPR051739666 (SPR)s40478-023-01577-y-e DE-627 ger DE-627 rakwb eng Schilling, Sandra verfasserin aut Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms. Alzheimer’s disease (dpeaa)DE-He213 Amyloid precursor protein (dpeaa)DE-He213 Familial Alzheimer disease (dpeaa)DE-He213 Beta Amyloid (dpeaa)DE-He213 Trafficking (dpeaa)DE-He213 Processing (dpeaa)DE-He213 Pradhan, Ajay aut Heesch, Amelie aut Helbig, Andrea aut Blennow, Kaj aut Koch, Christian aut Bertgen, Lea aut Koo, Edward H. aut Brinkmalm, Gunnar aut Zetterberg, Henrik aut Kins, Stefan aut Eggert, Simone aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 01. Juni (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:01 month:06 https://dx.doi.org/10.1186/s40478-023-01577-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 01 06
spelling	10.1186/s40478-023-01577-y doi (DE-627)SPR051739666 (SPR)s40478-023-01577-y-e DE-627 ger DE-627 rakwb eng Schilling, Sandra verfasserin aut Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms. Alzheimer’s disease (dpeaa)DE-He213 Amyloid precursor protein (dpeaa)DE-He213 Familial Alzheimer disease (dpeaa)DE-He213 Beta Amyloid (dpeaa)DE-He213 Trafficking (dpeaa)DE-He213 Processing (dpeaa)DE-He213 Pradhan, Ajay aut Heesch, Amelie aut Helbig, Andrea aut Blennow, Kaj aut Koch, Christian aut Bertgen, Lea aut Koo, Edward H. aut Brinkmalm, Gunnar aut Zetterberg, Henrik aut Kins, Stefan aut Eggert, Simone aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 01. Juni (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:01 month:06 https://dx.doi.org/10.1186/s40478-023-01577-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 01 06
allfields_unstemmed	10.1186/s40478-023-01577-y doi (DE-627)SPR051739666 (SPR)s40478-023-01577-y-e DE-627 ger DE-627 rakwb eng Schilling, Sandra verfasserin aut Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms. Alzheimer’s disease (dpeaa)DE-He213 Amyloid precursor protein (dpeaa)DE-He213 Familial Alzheimer disease (dpeaa)DE-He213 Beta Amyloid (dpeaa)DE-He213 Trafficking (dpeaa)DE-He213 Processing (dpeaa)DE-He213 Pradhan, Ajay aut Heesch, Amelie aut Helbig, Andrea aut Blennow, Kaj aut Koch, Christian aut Bertgen, Lea aut Koo, Edward H. aut Brinkmalm, Gunnar aut Zetterberg, Henrik aut Kins, Stefan aut Eggert, Simone aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 01. Juni (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:01 month:06 https://dx.doi.org/10.1186/s40478-023-01577-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 01 06
allfieldsGer	10.1186/s40478-023-01577-y doi (DE-627)SPR051739666 (SPR)s40478-023-01577-y-e DE-627 ger DE-627 rakwb eng Schilling, Sandra verfasserin aut Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms. Alzheimer’s disease (dpeaa)DE-He213 Amyloid precursor protein (dpeaa)DE-He213 Familial Alzheimer disease (dpeaa)DE-He213 Beta Amyloid (dpeaa)DE-He213 Trafficking (dpeaa)DE-He213 Processing (dpeaa)DE-He213 Pradhan, Ajay aut Heesch, Amelie aut Helbig, Andrea aut Blennow, Kaj aut Koch, Christian aut Bertgen, Lea aut Koo, Edward H. aut Brinkmalm, Gunnar aut Zetterberg, Henrik aut Kins, Stefan aut Eggert, Simone aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 01. Juni (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:01 month:06 https://dx.doi.org/10.1186/s40478-023-01577-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 01 06
allfieldsSound	10.1186/s40478-023-01577-y doi (DE-627)SPR051739666 (SPR)s40478-023-01577-y-e DE-627 ger DE-627 rakwb eng Schilling, Sandra verfasserin aut Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms. Alzheimer’s disease (dpeaa)DE-He213 Amyloid precursor protein (dpeaa)DE-He213 Familial Alzheimer disease (dpeaa)DE-He213 Beta Amyloid (dpeaa)DE-He213 Trafficking (dpeaa)DE-He213 Processing (dpeaa)DE-He213 Pradhan, Ajay aut Heesch, Amelie aut Helbig, Andrea aut Blennow, Kaj aut Koch, Christian aut Bertgen, Lea aut Koo, Edward H. aut Brinkmalm, Gunnar aut Zetterberg, Henrik aut Kins, Stefan aut Eggert, Simone aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 01. Juni (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:01 month:06 https://dx.doi.org/10.1186/s40478-023-01577-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 01 06
language	English
source	Enthalten in Acta Neuropathologica Communications 11(2023), 1 vom: 01. Juni volume:11 year:2023 number:1 day:01 month:06
sourceStr	Enthalten in Acta Neuropathologica Communications 11(2023), 1 vom: 01. Juni volume:11 year:2023 number:1 day:01 month:06
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Alzheimer’s disease Amyloid precursor protein Familial Alzheimer disease Beta Amyloid Trafficking Processing
isfreeaccess_bool	true
container_title	Acta Neuropathologica Communications
authorswithroles_txt_mv	Schilling, Sandra @@aut@@ Pradhan, Ajay @@aut@@ Heesch, Amelie @@aut@@ Helbig, Andrea @@aut@@ Blennow, Kaj @@aut@@ Koch, Christian @@aut@@ Bertgen, Lea @@aut@@ Koo, Edward H. @@aut@@ Brinkmalm, Gunnar @@aut@@ Zetterberg, Henrik @@aut@@ Kins, Stefan @@aut@@ Eggert, Simone @@aut@@
publishDateDaySort_date	2023-06-01T00:00:00Z
hierarchy_top_id	746066465
id	SPR051739666
language_de	englisch
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author	Schilling, Sandra
spellingShingle	Schilling, Sandra misc Alzheimer’s disease misc Amyloid precursor protein misc Familial Alzheimer disease misc Beta Amyloid misc Trafficking misc Processing Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity
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topic_title	Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity Alzheimer’s disease (dpeaa)DE-He213 Amyloid precursor protein (dpeaa)DE-He213 Familial Alzheimer disease (dpeaa)DE-He213 Beta Amyloid (dpeaa)DE-He213 Trafficking (dpeaa)DE-He213 Processing (dpeaa)DE-He213
topic	misc Alzheimer’s disease misc Amyloid precursor protein misc Familial Alzheimer disease misc Beta Amyloid misc Trafficking misc Processing
topic_unstemmed	misc Alzheimer’s disease misc Amyloid precursor protein misc Familial Alzheimer disease misc Beta Amyloid misc Trafficking misc Processing
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title	Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity
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title_full	Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity
author_sort	Schilling, Sandra
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author_browse	Schilling, Sandra Pradhan, Ajay Heesch, Amelie Helbig, Andrea Blennow, Kaj Koch, Christian Bertgen, Lea Koo, Edward H. Brinkmalm, Gunnar Zetterberg, Henrik Kins, Stefan Eggert, Simone
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doi_str_mv	10.1186/s40478-023-01577-y
title_sort	differential effects of familial alzheimer’s disease-causing mutations on amyloid precursor protein (app) trafficking, proteolytic conversion, and synaptogenic activity
title_auth	Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity
abstract	Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms. © The Author(s) 2023
abstractGer	Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms. © The Author(s) 2023
abstract_unstemmed	Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms. © The Author(s) 2023
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title_short	Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity
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