Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment

Franziska Rieche, Katia Carmine-Simmen, Burkhard Poeck, Doris Kretzschmar, Roland Strauss

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The β-amyloid precursor protein (APP) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. APP is cleaved by various secretases whereby sequential processing by the β- and γ-secretases produces the β-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N-terminal sAPPβ fragments and the APP intracellular domain (AICD). Alternative cleavage by α-secretase results in slightly longer secreted sAPPα fragments and the identical AICD. Whereas the AICD has been connected with transcriptional regulation, sAPPα fragments have been suggested to have a neurotrophic and neuroprotective role [1]. Moreover, expression of sAPPα in APP-deficient mice could rescue their deficits in learning, spatial memory, and long-term potentiation [2]. Loss of the Drosophila APP-like (APPL) protein impairs associative olfactory memory formation and middle-term memory that can be rescued with a secreted APPL fragment [3]. We now show that APPL is also essential for visual working memory. Interestingly, this short-term memory declines rapidly with age, and this is accompanied by enhanced processing of APPL in aged flies. Furthermore, reducing secretase-mediated proteolytic processing of APPL can prevent the age-related memory loss, whereas overexpression of the secretases aggravates the aging effect. Rescue experiments confirmed that this memory requires signaling of full-length APPL and that APPL negatively regulates the neuronal-adhesion molecule Fasciclin 2. Overexpression of APPL or one of its secreted N termini results in a dominant-negative interaction with the FASII receptor. Therefore, our results show that specific memory processes require distinct APPL products. Walking flies can memorize the path to a vanished landmark for about 4 s by integrating visual and idiothetic information about their own movements. Rieche et al. show that this memory is rapidly deteriorating with age and depends on amyloid precursor protein-like (APPL) signaling. Reducing cleavage of APPL ameliorates age-related memory deficits.

Original languageEnglish (US)
Pages (from-to)817-823.e3
JournalCurrent Biology
Volume28
Issue number5
DOIs
StatePublished - Mar 5 2018
Externally publishedYes

Fingerprint

Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
amyloid
Short-Term Memory
Drosophila
Data storage equipment
Amyloid
Memory Disorders
proteins
Diptera
Alzheimer Disease
Drosophila Proteins
Long-Term Potentiation
Alzheimer disease
Walking
Processing
Learning
Peptides
walking
adhesion

Keywords

  • age-related memory impairment
  • Amyloid Precursor Protein
  • central complex
  • Drosophila
  • Fasciclin 2
  • visual orientation
  • working memory

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment. / Rieche, Franziska; Carmine-Simmen, Katia; Poeck, Burkhard; Kretzschmar, Doris; Strauss, Roland.

In: Current Biology, Vol. 28, No. 5, 05.03.2018, p. 817-823.e3.

Research output: Contribution to journalArticle

Rieche, Franziska ; Carmine-Simmen, Katia ; Poeck, Burkhard ; Kretzschmar, Doris ; Strauss, Roland. / Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment. In: Current Biology. 2018 ; Vol. 28, No. 5. pp. 817-823.e3.
@article{205425ef5f6641f890ef51cfb0f70c1a,
title = "Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment",
abstract = "The β-amyloid precursor protein (APP) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. APP is cleaved by various secretases whereby sequential processing by the β- and γ-secretases produces the β-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N-terminal sAPPβ fragments and the APP intracellular domain (AICD). Alternative cleavage by α-secretase results in slightly longer secreted sAPPα fragments and the identical AICD. Whereas the AICD has been connected with transcriptional regulation, sAPPα fragments have been suggested to have a neurotrophic and neuroprotective role [1]. Moreover, expression of sAPPα in APP-deficient mice could rescue their deficits in learning, spatial memory, and long-term potentiation [2]. Loss of the Drosophila APP-like (APPL) protein impairs associative olfactory memory formation and middle-term memory that can be rescued with a secreted APPL fragment [3]. We now show that APPL is also essential for visual working memory. Interestingly, this short-term memory declines rapidly with age, and this is accompanied by enhanced processing of APPL in aged flies. Furthermore, reducing secretase-mediated proteolytic processing of APPL can prevent the age-related memory loss, whereas overexpression of the secretases aggravates the aging effect. Rescue experiments confirmed that this memory requires signaling of full-length APPL and that APPL negatively regulates the neuronal-adhesion molecule Fasciclin 2. Overexpression of APPL or one of its secreted N termini results in a dominant-negative interaction with the FASII receptor. Therefore, our results show that specific memory processes require distinct APPL products. Walking flies can memorize the path to a vanished landmark for about 4 s by integrating visual and idiothetic information about their own movements. Rieche et al. show that this memory is rapidly deteriorating with age and depends on amyloid precursor protein-like (APPL) signaling. Reducing cleavage of APPL ameliorates age-related memory deficits.",
keywords = "age-related memory impairment, Amyloid Precursor Protein, central complex, Drosophila, Fasciclin 2, visual orientation, working memory",
author = "Franziska Rieche and Katia Carmine-Simmen and Burkhard Poeck and Doris Kretzschmar and Roland Strauss",
year = "2018",
month = "3",
day = "5",
doi = "10.1016/j.cub.2018.01.077",
language = "English (US)",
volume = "28",
pages = "817--823.e3",
journal = "Current Biology",
issn = "0960-9822",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment

AU - Rieche, Franziska

AU - Carmine-Simmen, Katia

AU - Poeck, Burkhard

AU - Kretzschmar, Doris

AU - Strauss, Roland

PY - 2018/3/5

Y1 - 2018/3/5

N2 - The β-amyloid precursor protein (APP) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. APP is cleaved by various secretases whereby sequential processing by the β- and γ-secretases produces the β-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N-terminal sAPPβ fragments and the APP intracellular domain (AICD). Alternative cleavage by α-secretase results in slightly longer secreted sAPPα fragments and the identical AICD. Whereas the AICD has been connected with transcriptional regulation, sAPPα fragments have been suggested to have a neurotrophic and neuroprotective role [1]. Moreover, expression of sAPPα in APP-deficient mice could rescue their deficits in learning, spatial memory, and long-term potentiation [2]. Loss of the Drosophila APP-like (APPL) protein impairs associative olfactory memory formation and middle-term memory that can be rescued with a secreted APPL fragment [3]. We now show that APPL is also essential for visual working memory. Interestingly, this short-term memory declines rapidly with age, and this is accompanied by enhanced processing of APPL in aged flies. Furthermore, reducing secretase-mediated proteolytic processing of APPL can prevent the age-related memory loss, whereas overexpression of the secretases aggravates the aging effect. Rescue experiments confirmed that this memory requires signaling of full-length APPL and that APPL negatively regulates the neuronal-adhesion molecule Fasciclin 2. Overexpression of APPL or one of its secreted N termini results in a dominant-negative interaction with the FASII receptor. Therefore, our results show that specific memory processes require distinct APPL products. Walking flies can memorize the path to a vanished landmark for about 4 s by integrating visual and idiothetic information about their own movements. Rieche et al. show that this memory is rapidly deteriorating with age and depends on amyloid precursor protein-like (APPL) signaling. Reducing cleavage of APPL ameliorates age-related memory deficits.

AB - The β-amyloid precursor protein (APP) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. APP is cleaved by various secretases whereby sequential processing by the β- and γ-secretases produces the β-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N-terminal sAPPβ fragments and the APP intracellular domain (AICD). Alternative cleavage by α-secretase results in slightly longer secreted sAPPα fragments and the identical AICD. Whereas the AICD has been connected with transcriptional regulation, sAPPα fragments have been suggested to have a neurotrophic and neuroprotective role [1]. Moreover, expression of sAPPα in APP-deficient mice could rescue their deficits in learning, spatial memory, and long-term potentiation [2]. Loss of the Drosophila APP-like (APPL) protein impairs associative olfactory memory formation and middle-term memory that can be rescued with a secreted APPL fragment [3]. We now show that APPL is also essential for visual working memory. Interestingly, this short-term memory declines rapidly with age, and this is accompanied by enhanced processing of APPL in aged flies. Furthermore, reducing secretase-mediated proteolytic processing of APPL can prevent the age-related memory loss, whereas overexpression of the secretases aggravates the aging effect. Rescue experiments confirmed that this memory requires signaling of full-length APPL and that APPL negatively regulates the neuronal-adhesion molecule Fasciclin 2. Overexpression of APPL or one of its secreted N termini results in a dominant-negative interaction with the FASII receptor. Therefore, our results show that specific memory processes require distinct APPL products. Walking flies can memorize the path to a vanished landmark for about 4 s by integrating visual and idiothetic information about their own movements. Rieche et al. show that this memory is rapidly deteriorating with age and depends on amyloid precursor protein-like (APPL) signaling. Reducing cleavage of APPL ameliorates age-related memory deficits.

KW - age-related memory impairment

KW - Amyloid Precursor Protein

KW - central complex

KW - Drosophila

KW - Fasciclin 2

KW - visual orientation

KW - working memory

UR - http://www.scopus.com/inward/record.url?scp=85042328035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042328035&partnerID=8YFLogxK

U2 - 10.1016/j.cub.2018.01.077

DO - 10.1016/j.cub.2018.01.077

M3 - Article

C2 - 29478851

AN - SCOPUS:85042328035

VL - 28

SP - 817-823.e3

JO - Current Biology

JF - Current Biology

SN - 0960-9822

IS - 5

ER -